US8853437B2 - Anti-inflammatory compounds - Google Patents
Anti-inflammatory compounds Download PDFInfo
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- US8853437B2 US8853437B2 US13/202,489 US201013202489A US8853437B2 US 8853437 B2 US8853437 B2 US 8853437B2 US 201013202489 A US201013202489 A US 201013202489A US 8853437 B2 US8853437 B2 US 8853437B2
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- C12P7/6436—Fatty acid esters
Definitions
- the present invention relates to a novel anti-inflammatory compound.
- An inflammatory disease in a modern era, is one of the important disease fields for which countermeasure is necessary and, as a modern anti-inflammatory drug, representatively, substances such as a steroid agent, and aspirin and ibuprofen called non-steroid anti-inflammatory drugs (NSAIDS) are used.
- a modern anti-inflammatory drug representatively, substances such as a steroid agent, and aspirin and ibuprofen called non-steroid anti-inflammatory drugs (NSAIDS) are used.
- NSAIDS non-steroid anti-inflammatory drugs
- the steroid agent since the steroid agent has a high effect, it is used as a therapeutic for any of acute and chronic inflammatory diseases in the clinical site, but a problem such as acquisition of resistance due to frequent use, a side effect etc. has been pointed out.
- Non-Patent Documents 1 and 2 Since NSAIDS have an antipyretic analgesic action, it has been used as symptomatic therapy, but it has also been known that in NSAIDS, due to ingestion for a long term, a disorder is generated in a digestive tract, a cardiac disease risk is increased, and progression of inflammatory tissue damage occurs, and this has become a serious problem (Non-Patent Documents 1 and 2).
- Non-Patent Documents 3 and 4 a substance having hydroxyl groups at the 18-position and the 5-position of eicosapentaenoic acid (EPA) called Resolvin such as Resolvin E1 (RvE1; 5S,12R,18R-trihydroxyeicosapentaenoic acid), and a derivative thereof, and a substance having hydroxyl groups at the 10-position and the 17-position of docosahexaenoic acid (DHA) called Protectin D1, and a derivative thereof have an anti-inflammatory activity (Non-Patent Documents 3 and 4).
- Resolvin such as Resolvin E1 (RvE1; 5S,12R,18R-trihydroxyeicosapentaenoic acid)
- DHA docosahexaenoic acid
- An object of the present invention is to provide a compound having a novel structure for overcoming the aforementioned defects of conventional steroid agents and NSAIDs.
- the present invention provides the followings:
- P 1 and P 2 are each independently a protective group, a hydrogen atom, alkyl, a hydroxyl group or a substituted hydroxyl group or a combination thereof, when
- R 1 and R 2 are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted branched or non-branched alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted branched or non-branched alkylaryl group or a combination thereof;
- X is —C(O)OR 3 , —C(O)NR 4 R 5 , —C(O)H, —C(NH)NR 4 R 5 , —C(S)H, —C(S)OR 3 , —C(S)NR 4 R 5 , or —CN;
- R 3 is hydrogen, a protective group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle or a group of the formula: —NR a R b (wherein R a and R b are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
- R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycle, or R 4 and R 5 may be taken together with an adjacent nitrogen atom to form a substituted or unsubstituted nitrogen-containing heterocyclic ring; and
- double bond configurations of the compound can be each independently any of cis or trans.
- a neutrophil suppressing agent comprising the compound or pharmaceutically acceptable salt or solvate according to Item 1 or 2.
- a pharmaceutical comprising the compound or pharmaceutically acceptable salt or solvate according to Item 1 or 2.
- the pharmaceutical according to Item 4 wherein the pharmaceutical is used for treating or preventing a disease, a disorder or a state which is improved by suppressing neutrophil selected from pulmonary diseases selected from pulmonary distress syndrome, adult respiratory distress syndrome, and chronic obstructive pulmonary disease (COPD); ischemic diseases selected from ischemic cardiac disease, ischemic renal disease, ischemic brain disease and ischemic hepatic disease; inflammatory diseases; stress related diseases selected from erosive gastritis, gastric ulcer, duodenal ulcer, bronchial asthma, ulcerative colitis, arteriosclerosis, Crohn disease, malignant tumor, ovarian cyst, salpingitis, hysteromyoma, endometriosis, spontaneous abortion, gestosis, infertility and dysmenorrhea.
- a method of treating or preventing an inflammatory disease comprising the step of administering the compound or pharmaceutically acceptable salt or solvate according to Item 1 or 2 to a subject in need of the treatment or the prevention.
- Resolvin E1, Resolvin E2 and Protectin D1 are excluded.
- synthesized compounds e.g., compounds synthesized with an enzyme; 11,18-diHEPE and 17,18-diHEPE correspond thereto
- a pair of a parent mass and a child mass of MRM can be optimized (optimization of collision energy) from measured values of MS/MS.
- MRM for the purpose of detection is performed by setting hypothetical conditions.
- the present invention unexpectedly remarkably suppresses infiltration into tissues and activation of neutrophil found at the time of acute inflammation.
- the compound of the present invention is a compound which has not been conventionally known. Therefore, utility as a new therapeutic is provided.
- the compound of the present invention since it has been found in the present invention that the compound of the present invention is also found in a living body, the compound of the present invention is expected to be a therapeutic having little side effect in administration for a medium and long term. In addition, since the compound of the present invention is different from steroid agents and NSAIDs in its action, the compound of the present invention is expected to have an effect as an anti-inflammatory agent by joint use with the existing steroid agents, etc.
- FIG. 1A is a view showing the principle of multiple reaction monitoring (MRM).
- MRM multiple reaction monitoring
- FIG. 1B shows an example of a solvent gradient used in MRM of the present invention.
- FIG. 1C is a list of polyunsaturated fatty acid (PUFA) metabolites to be measured by the conventional MRM.
- EET represents epoxy eicosatrienoic acid
- ETE represents eicosatetraenoic acid
- HDoPE represents hydroxy docosapentaenoic acid
- DPE represents docosapentaenoic acid.
- FIG. 2A-1 shows incubation of peritoneal exudate cells (PEC) at an inflammation early stage (after 4 hours) with 18-hydroxy eicosapentaenoic acid (HEPE).
- An asterisk indicates a peak of a metabolite including respective isomers. From the left side, an asterisk indicates Resolvin E1, Resolvin E2, and 8,18-dihydroxy eicosapentaenoic acid (diHEPE) in this order.
- FIG. 2B-1 shows incubation of PEC at an inflammation later stage (after 48 hours) with 18-HEPE.
- An asterisk indicates a peak of a metabolite including respective isomers. From the left side, an asterisk indicates Resolvin E1, Resolvin E2, and 8,18-diHEPE in this order.
- FIG. 2D shows the analysis results of each metabolite generated as the result of incubation of 18-HEPE with eosinophil.
- An asterisk indicates a peak of each main metabolite. From the left upper side to the right upper side, an asterisk indicates Resolvin E1, Resolvin E2, and 8,18-diHEPE in this order and, from the left lower side to the right lower side, an asterisk indicates 11,18-diHEPE, 12,18-diHEPE and 17,18-diHEPE in this order.
- FIG. 2E shows the analysis result and relative quantitation of each metabolite generated as the result of incubation of 20-HDoHE with eosinophil.
- An asterisk indicates a peak of each main metabolite. From the left upper side to the right upper side, an asterisk indicates 10,20-diHDoHE, and 13,20-diHDoHE in this order and, from the left lower side to the right lower side, an asterisk indicates 14,20-diHDoHE and 19,20-diDoHE in this order.
- FIG. 2F shows a metabolism route using 18-HEPE which is a metabolite of eicosapentaenoic acid (EPA) as an origin.
- EPA eicosapentaenoic acid
- FIG. 3B shows (a) mass spectroscopy (MS/MS) and (b) light absorption spectrum of peaks 1 to 4 of Example 3, and (c) structure of 11,18-diHEPE.
- FIG. 3C shows (a) mass spectroscopy (MS/MS) and (b) light absorption spectrum of peaks 5 and 6 of Example 3, and (c) structure of 17,18-diHEPE.
- FIG. 4A shows assessment of physiological activity of an 18-HEPE-derived metabolite (17,18-diHEPE) in a zymosan peritonitis model.
- physiological saline control
- 10 ng of 17,18-diHEPE and 10 ⁇ g of dexamethasone are injected into a mouse tail vein, respectively, and 1 mg of zymosan is intraperitoneally administered after 5 minutes to initiate peritonitis.
- FIG. 4B shows assessment of physiological activity of an 18-HEPE-derived metabolite (17,18-diHEPE) in an acute lung damage model. From the left side, the total number of cells (a), the number of neutrophil (b) and the number of macrophage (c) which have infiltrated into lung at the time point of 12 hours after non-treatment (intact), intrabronchial hydrochloric acid administration (saline/HCl), and intrabronchial hydrochloric acid administration after tail vein administration of 10 ng of 17,18-diHEPE (17,18diHEPE/HCl) are shown. The average of 3 or more times experiments is taken, respectively, and the value is shown as an average ⁇ SEM. * represents p ⁇ 0.05 for saline/HCl.
- FIG. 4C shows assessment of physiological activity of peaks 5 and 6 in a zymosan peritonitis model.
- physiological saline and dexamethasone are used as a control.
- the gray column indicates neutrophil
- the black column indicates lymphocyte
- the white column indicates macrophage.
- FIG. 4D shows that activity of a synthesized compound in a peritonitis model is dose-dependent. The result is shown as an average+SD, * represents p ⁇ 0.05 for physiological saline, and ** represents p ⁇ 0.001 for physiological saline.
- FIG. 4E shows assessment of activity of a synthesized compound in an acute lung damage model. From the left side, the number of neutrophil which have infiltrated into lung at the time point of 12 hours after non-treatment (intact), intrabronchial hydrochloric acid administration (saline/HCl), and intrabronchial hydrochloric acid administration after tail vale administration of 10 ng of peak 6 (Peak 6/HCl) are shown.
- FIG. 4F is a graph showing a relationship of dose-decrease in the neutrophil number for studying a dose of IC 40 .
- FIG. 6 shows (A) reverse phase HPLC chromatogram of a sample obtained by incubation of 20-HDoHE with 8-LOX, and (B) mass spectroscopy (MS/MS) of a peak 1 and the structure of 10,20-diHDoHE.
- FIG. 8 shows (A) reverse phase HPLC chromatogram of a sample obtained by incubation of 14-HpEPE with sLOX, and (B) mass spectroscopy (MS/MS) of peak 1 and the structure of 14,20-diHDoHE.
- FIG. 9A shows a metabolism route using 12-HpEPE which is a metabolite of eicosapentaenoic acid (EPA) as an origin.
- EPA eicosapentaenoic acid
- FIG. 10 shows comparison of activities regarding a variety of compounds.
- FIG. 11 shows the analysis results of each metabolite generated as the result of incubation of 18-HEPE with human eosinophil.
- An asterisk indicates a peak of each main metabolite. From the left upper side to the right upper side, an asterisk indicates Resolvin E1, Resolvin E2, and 8,18-diHEPE in this order and, from the left lower side to the right lower side, an asterisk indicates 11,18-diHEPE, 12,18-diHEPE and 17,18-diHEPE in this order.
- FIG. 12 shows the analysis results of each metabolite generated as the result of incubation of 20-HDoHE with human eosinophil.
- An asterisk indicates a peak of each main metabolite. From the left upper side to the right upper side, an asterisk indicates 10,20-diHDoHE, and 13,20-diHDoHE in this order and, from the left upper side to the right upper side, an asterisk indicates 14,20-diHDoHE and 19,20-diDoHE in this order.
- CCR chemokine (C—C motif)-receptor
- DHA docosahexaenoic acid
- DPA docosapentaenoic acid
- EpDPE epoxy docosapentaenoic acid
- EpETE epoxy eicosatetraenoic acid
- HDoHE hydroxy docosahexaenoic acid
- HEPE hydroxy eicosapentaenoic acid
- HpDoHE hydroperoxy docosapentaenoic acid
- HpEPE hydroperoxy eicosapentaenoic acid
- PBS phosphate buffered saline
- PUFA polyunsaturated fatty acid
- halogen means fluorine, chlorine, bromine and iodine. Fluorine, chlorine, and bromine are preferable.
- alkyl refers to a saturated or unsaturated, branched, straight or cyclic monovalent hydrocarbon group having carbon atoms in the referred number (that is, C1-C6 means 1 to 6 carbon atoms), which is derived by removing one hydrogen atom from a single carbon atom of a parent alkane, as itself, or as a part of other substituents.
- the alkyl includes a straight or branched monovalent hydrocarbon group having 1 to 8 carbon atoms.
- Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, and n-octyl.
- Preferable examples thereof include C1-C6 alkyl.
- Further preferable examples thereof include C1-C4 alkyl.
- the alkyl means “alkyl” having carbon atoms in a range of the number.
- alkenyl refers to an unsaturated and branched, straight, or cyclic hydrocarbon group, having at least one carbon-carbon double bond, which is derived by removing one hydrogen atom from a single carbon atom of a parent alkene, as itself, or as a part of other substituents.
- the alkenyl includes a straight or branched monovalent hydrocarbon group having 2 to 8 carbon atoms, and having one or two or more double bonds. The group may have either of cis configuration or trans configuration regarding a double bond. Examples thereof include vinyl, allyl, 1-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, and 2-octenyl.
- Preferable examples thereof include C2-C6 alkenyl.
- Further preferable examples thereof include C2-C4 alkenyl.
- alkynyl includes a straight or branched monovalent hydrocarbon group having 2 to 8 carbon atoms and having one or two or more triple bonds. Examples thereof include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-hexynyl, 2-heptynyl, and 2-octynyl. Preferable examples thereof include C2-C6 alkynyl. Further preferable examples thereof include C2-C4 alkynyl.
- diyl of alkyl, alkenyl or alkynyl refers to a saturated or unsaturated, branched, straight or cyclic divalent hydrocarbon group having carbon atoms in the referred number (that is, C1-C6 means 1 to 6 carbon atoms), which is derived by removing one hydrogen atom from each of two different carbon atoms of parent alkane, alkene or alkyne, or removing two hydrogen atoms from a single carbon atom of parent alkane, alkene or alkyne, as itself, or as a part of other substituents.
- a bond can be formed with atoms, in which each valence of a center of two monovalent groups or a center of a divalent group is the same or different.
- the diyl group include, but are not limited to, the followings: methanediyl; ethyldiyls such as ethane-1,1-diyl, ethane-1,2-diyl, ethene-1,1-diyl, or ethene-1,2-diyl; propyldiyl such as propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl, propane-1,3-diyl, cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, prop-1-ene-1,1-diyl, prop-1-ene-1,2-diyl, prop-2-ene-1,2-diyl, prop-1-ene-1
- alkyldiyl alkenyldiyl and/or alkynyldiyl is used.
- alkylidene is used.
- an alkyldiyl group is (C1-C6) alkyldiyl.
- a saturated non-cyclic alkanyldiyl group in which a center of group is on carbon at an end for example, methanediyl (methano); ethane-1,2-diyl (ethano); propane-1,3-diyl (propano); butane-1,4-diyl (butano); etc. are also preferable (also referred to as “alkyleno”).
- cycloalkyl refers to an unsaturated and branched, straight or cyclic hydrocarbon group having at least one carbon-carbon triple bond, which is derived by removing one hydrogen atom from a single carbon atom of parent alkene, as itself, or as a part of other substituents.
- cycloalkyl includes cycloalkyl having 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferable examples thereof include C3-C6 cycloalkyl.
- cycloalkenyl includes cycloalkenyl having 3 to 8 carbon atoms. Examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, and preferable examples thereof include C3-C6 cycloalkenyl.
- alkoxy examples include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, 2-pentyloxy, 3-pentyloxy, n-hexyloxy, isohexyloxy, 2-hexyloxy, 3-hexyloxy, n-heptyloxy, and n-octyloxy.
- Preferable examples thereof include C1-C6 alkyloxy.
- Further preferable examples thereof include C1-C4 alkyloxy.
- the alkoxy means “alkoxy” having carbon atoms in a range of the number.
- alkylsulfonyl examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, 2-pentylsulfonyl, 3-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, 2-hexylsulfonyl, 3-hexylsulfonyl, n-heptylsulfonyl, and n-octylsulfonyl.
- Preferable examples thereof include C1
- alkyloxycarbonyl examples include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, and n-pentyloxycarbonyl.
- Preferable examples thereof include C1-C4 alkyloxycarbonyl.
- Particularly preferable examples thereof include C1-C2 alkyloxycarbonyl.
- acyl includes formyl, alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, and heterocyclecarbonyl. Examples thereof include acetyl, propionyl, butyroyl, and benzoyl.
- lower alkyl includes straight or branched alkyl having 1 to 6 carbon atoms, and preferably 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, and isohexyl.
- lower alkyl part of “lower alkoxy”, “hydroxy lower alkyl”, “hydroxy lower alkoxy”, “lower alkoxycarbonyl”, “lower alkylamino”, “lower alkoxy lower alkoxy”, “lower alkylcarbamoyl”, “hydroxy lower alkylcarbamoyl”, “lower alkoxyimino”, “lower alkylthio”, “lower alkylsulfonyl”, “lower alkylsulfonyloxy”, “lower alkylsulfamoyl”, and “lower alkylsulfinyl” is also the same as the above “lower alkyl”.
- substituted or unsubstituted lower alkyl may be substituted, and may be preferably substituted with one or more groups selected from a substituent group ⁇ .
- the substituent group ⁇ is a group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, imino, hydroxyimino, lower alkoxyimino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, a carbocyclic group and a heterocyclic group.
- lower alkenyl includes a straight or branched alkenyl having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, and having one or more double bonds at an arbitrary position.
- Specific examples thereof include vinyl, aryl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl.
- lower alkynyl includes a straight or branched alkynyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms, and having one or more triple bonds at an arbitrary position. Specific examples thereof include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. These may further have a double bond at an arbitrary position.
- “carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl, and non-aromatic condensed carbocyclic group, etc.
- substituted or unsubstituted amino includes amino which may be substituted at one or two positions with the “alkyl” described above, the “aryl” described later, the “heteroaryl” described later, the “heterocycle” described later, the “acyl” described above, the “alkyloxycarbonyl” described above, the “alkylsulfonyl” described above, the “arylsulfonyl” described later, the “heteroarylsulfonyl” described later, and the “heterocyclesulfonyl” described later.
- Examples thereof include amino, methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, benzylamino, acetylamino, benzoylamino, methyloxycarbonylamino, and methylsulfonylamino.
- Preferable examples thereof include amino, methylamino, dimethylamino, ethylmethylamino, diethylamino, acetylamino, and methylsulfonylamino.
- substituted or unsubstituted carbamoyl includes substituted or unsubstituted aminocarbonyl in which the substituted or unsubstituted amino part is the above “substituted or unsubstituted amino”.
- examples thereof include carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-benzylcarbamoyl, N-acetylcarbamoyl, and N-methylsulfonylcarbamoyl.
- Preferable examples thereof include carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, and N-methylsulfonylcarbamoyl.
- aryl includes a monocyclic or condensed cyclic aromatic hydrocarbon. This may be condensed at possible all positions with the “cycloalkyl” described above, the “heteroaryl” described later, and the “heterocycle” described later. When the aryl is any of monocyclic and a condensed ring, the aryl can bind at all possible positions. Examples thereof include phenyl, 1-naphthyl, 2-naphthyl, anthryl, tetrahydronaphthyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl. Preferable examples thereof include phenyl, 1-naphthyl, and 2-naphthyl. Further preferable examples thereof include phenyl.
- heterocyclic or “heterocycle” includes a non-aromatic heterocyclic group which may contain 1 to 4 heteroatoms such as an oxygen atom, a sulfur atom and a nitrogen atom in a ring, and may have a combined hand at a replaceable arbitrary position.
- a non-aromatic heterocyclic group may be further crosslinked with an alkyl chain having 1 to 4 carbon atoms, or may be condensed with cycloalkane (5- to 6-membered ring is preferable), or a benzene ring. It may be saturated or unsaturated as far as it is non-aromatic.
- pyrrolinyl e.g., 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl
- pyrrolidinyl e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl
- pyrrolidinone imidazolinyl (e.g., 1-imidalinyl, 2-imidazolinyl, 4-imidazolinyl), imidazolidinyl (e.g., 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl), imidazolidinone, pyrazolinyl (e.g., 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl), pyrazolidinyl (e.g.
- heteroaryl includes a 5- to 6-membered aromatic ring containing one or more heteroatoms arbitrarily selected from an oxygen atom, a sulfur atom or a nitrogen atom, etc. in a ring.
- Heteroaryl includes an aromatic cyclic group among the “heterocyclic groups”. This may be condensed at possible all positions with the “cycloalkyl” described above, the “aryl” described above, the “heterocycle” described above, or other heteroaryls. When the heteroaryl is any of monocyclic and a condensed ring, it can bind at all possible positions.
- Examples thereof include pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl
- heterocyclic group includes a heterocyclic group having one or more heteroatoms arbitrarily selected from oxygen, sulfur and nitrogen, etc. in a ring and, specific examples thereof include 5- to 6-membered heteroaryls such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, or thiadiazolyl; a non-aromatic heterocyclic group such as dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl,
- alkylene means straight or branched alkylene having 1 to 10 carbon atoms, and examples thereof include methylene, 1-methylmethylene, 1,1-dimethylmethylene, ethylene, 1-methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1,1-diethylethylene, 1,2-diethylethylene, 1-ethyl-2-methylethylene, trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-diethyltrimethylene, 1,2-diethyltrimethylene, 2,2-diethyltrimethylene, 2-ethyl-2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene, trimethylene, 1-methyl
- alkenylene means straight or branched alkenylene having 2 to 10 carbon atoms, and examples thereof include ethenylene, 1-methylethenylene, 1-ethylethenylene, 1,2-dimethylethenylene, 1,2-diethylethenylene, 1-ethyl-2-methylethenylene, propenylene, 1-methyl-2-propenylene, 2-methyl-2-propenylene, 1,1-dimethyl-2-propenylene, 1,2-dimethyl-2-propenylene, 1-ethyl-2-propenylene, 2-ethyl-2-propenylene, 1,1-diethyl-2-propenylene, 1,2-diethyl-2-propenylene, 1-butenylene, 2-butenylene, 1-methyl-2-butenylene, 2-methyl-2-butenylene, 1,1-dimethyl-2-butenylene, and 1,2-dimethyl-2-butenylene. Particularly, straight or branched alkenylene,
- alkynylene includes a straight or branched divalent carbon chain having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, which has a triple bond at an arbitrary position and, further, may have a double bond. Specific examples thereof include ethynylene, propynylene, butynylene, pentynylene and hexynylene.
- alkyl part of “alkylcarbonyl” means the above “alkyl”.
- alkenyl parts of “alkenyloxy” and “alkenylcarbonyl” mean the above “alkenyl”.
- aryl parts of “aryloxy” and “arylcarbonyl” mean the above “aryl”.
- heteroaryl part of “heteroarylcarbonyl” means the above “heteroaryl”.
- heterocycle part of “heterocyclecarbonyl” means the above “heterocycle”.
- aryl part of “arylsulfonyl” means the above “aryl”.
- heteroaryl part of “heteroarylsulfonyl” means the above “heteroaryl”.
- heterocycle part of “heterocyclesulfonyl” means the above “heterocycle”.
- examples of a typical heteroatom and/or heteroatom group which can replace a carbon atom include, but are not limited to, the followings: —O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O) 2 —, —S(O)NR′—, —S(O) 2 NR′—, etc., and a combination thereof.
- each R′ is independently hydrogen or (C1-C6) alkyl.
- aromatic ring system refers to an unsaturated ring or a polycyclic ring system having a conjugated ⁇ electron system.
- a condensed ring system in which one or more rings are aromatic, and one or more rings are saturated or unsaturated, for example, fluorene, indane, indene, phenalene, and tetrahydronaphthalene are specifically included in definition of “aromatic ring system”.
- Typical examples of the parent aromatic ring system include, but are not limited to, the followings: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azlene, benzene, chrysene, coronene, fluorancene, fluorene, hexacene, hexaphene, hexylene, indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, tetrahydronaphthalene, triphenylene, and trinaphthalene
- non-aromatic condensed carbocyclic group includes a group in which two or more cyclic groups selected from the above “cycloalkyl”, “cycloalkenyl” and “aryl” are condensed and, specific examples thereof include indanyl, indenyl, tetrahydronaphthyl and fluorenyl.
- examples of a substituent of “substituted or unsubstituted carbocyclic group” and “substituted or unsubstituted heterocyclic group” include arbitrary substituents, preferably, one or more groups selected from the group consisting of lower alkyl and a substituent group ⁇ .
- alkyloxy refers to a group of the formula —OR′′
- alkylamine refers to a group of the formula —NHR′′
- dialkylamine refers to a group of NR′′R′′, wherein each R′′ is independently alkyl.
- haloalkoxy or “haloalkyloxy” refers to a group of the formula —OR′′′, wherein R′′′ is haloalkyl.
- solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof and, for example, includes a solvate with an organic solvent (e.g., alcoholate (e.g., ethanolate)), and a hydrate.
- an organic solvent e.g., alcoholate (e.g., ethanolate)
- a hydrate When a hydrate is formed, it may be coordinated with any number of water molecules. Examples of the hydrate include monohydrate, and dihydrate.
- prodrug refers to a substance which is modified so that it does not exhibit the drug action in an original form, or only exhibits very weak activity, but exhibits pharmacological activity for the first time or increases pharmacological activity by being metabolized in a living body, taking advantages of a metabolism mechanism of a living body.
- pharmaceutically acceptable prodrug of the present invention any form known in the art can be adopted. Examples of the prodrug include an ester and an amide, in addition to a salt and a solvate.
- a term of “pharmaceutically acceptable salt, ester, amide, and prodrug”, as used herein, refers to carboxylate, amino acid adduct salt, ester, amide, and prodrug of the compound of the present specification, and this refers to a substance which is in a range of normal medical determination, is suitable for use in contact with a tissue of a patient without excessive toxicity, inflammation and allergic response, and is effective for the intended use of the compound of the present invention.
- salt refers to relatively non-toxic inorganic or organic acid addition salts of the compound of the present invention. These salts can be prepared by separately reacting purified compounds with a suitable organic or inorganic acid, transiently or in the form of a free base, during final isolation and purification of the compound, and isolating the thus formed salts.
- Examples of the pharmaceutically acceptable salt of the compound of the present invention include the following salts.
- Examples of a pharmaceutically acceptable basic salt of the compound of the present invention include alkali metal salts such as a sodium salt, and a potassium salt; alkaline earth metal salts such as a calcium salt, and a magnesium salt; ammonium salts; aliphatic amine salts such as a trimethylamine salt, a triethylamine salt, a dicyclohexylamine salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a procaine salt, a meglumine salt, a diethanolamine salt and an ethylenediamine salt; aralkylamine salts such as N,N-dibenzylethylenediamine, and a benethamine salt; heterocyclic aromatic amine salts such as a pyridine salt, a picoline salt, a quinoline salt, and an isoquinoline salt; quaternary ammonium salts such as a tetramethylammonium salt, a tetraethy
- Examples of a pharmaceutically acceptable acidic salt of the compound of the present invention include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, and perchlorate; organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartarate, malate, citrate, and ascorbate; sulfonic acid salts such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate; acidic amino acid salts such as aspartate, and glutamate; etc.
- inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, and perchlorate
- organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartarate, malate, citrate, and ascorbate
- hydrochloric acid phosphoric acid, tartaric acid or methanesulfonic acid is preferable.
- These salts can be formed by a generally performed method.
- a term of “pharmaceutically acceptable ester” refers to relatively non-toxic esterified products of the compound of the present invention. These esters can be prepared by separately reacting purified compounds with a suitable esterifying agent, in situ, or in the form of a free acid form or hydroxyl, during final isolation and purification of the compound. Carboxylic acid can be converted into an ester via treatment with an alcohol in the presence of a catalyst. It is further intended that this term includes a lower hydrocarbon group which can be solvated under the physiological conditions, for example, an alkyl ester, a methyl ester, an ethyl ester and a propyl ester.
- isomer is used in the same meaning as that generally used in the art, and refers to substances which have the same molecular formula, but are different in a structural formula and a nature.
- the isomer used in the present invention is not limited to a particular isomer, but includes all possible isomers (e.g., keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, diastereomer, geometric isomer, steric isomer, cis-trans isomer, conformational isomer and rotamer, etc.) and racemates. It is to be understood that one or more chiral centers are present in each of the compound of the present invention.
- the present invention includes all stereochemistry types of each compound, for example, an enantiomer, a diastereomer and a racemic compound.
- an asymmetric carbon atom is present, more than one steric isomers are possible, and it is intended that all possible isomers are included in expression of an indicated structure.
- active (R) and (S) isomers may be separated using a conventional technique known to a person skilled in the art. It is intended that the present invention includes possible diastereomers as well as racemic compounds and optically resolved isomers.
- Hydroxyl in the compound of the present invention can be protected with a variety of protective groups such as those known in the art.
- protective group refers to a group of atoms which, when bound to a reactive functional group in a molecule, masks, decreases or hampers reactivity of the functional group. Typically, the protective group may be selectively removed as desired during a process of synthesis. Examples of the protective group can be seen in Greene and Wuts, Protective Groups in Organic Chemistry, third edition, 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY.
- Examples of a representative nitrogen protective group include, but are not limited to, the followings: formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and a substituted trityl group, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”), etc.
- Examples of a representative hydroxyl protective group include, but are not limited to, those in which a hydroxyl group has been acetylated (esterified) or alkylated, for example, benzyl ether and trityl ether, as well as alkyl ether, tetrahydropyranyl ether, trialkylsilyl ether (e.g., a TMS group or a TIPPS group), glycol ether, for example, ethylene glycol and propylene glycol derivatives, and allyl ether.
- a person skilled in the art can easily determine which protective group can be useful for protecting a hydroxyl group.
- a standard method is known in the art, and is more completely described in documents.
- a suitable protective group can be selected by a person skilled in the art, and is described in Green and Wuts, “Protecting Groups in Organic Synthesis”, John Wiley and Sons, Chapters 5 and 7, 1991, and this teaching is incorporated in the present specification by reference.
- a preferable protective group includes methyl and ethyl ether, a TMS or TIPPS group, acetic acid (ester) or a propionic acid group, and glycol ether, for example, ethylene glycol and propylene glycol derivatives.
- one or more hydroxyl groups are treated with a mild base, for example, triethylamine in the presence of an acid chloride or silyl chloride, and therefore, a reaction between hydroxyl ions and a halide can be made easy.
- a mild base for example, triethylamine
- alkyl halide is reacted with hydroxyl ions (generated by a base such as lithium diisopropylamide), and therefore, formation of an ether can be made easy.
- Resolvins/Protectins refer to the followings: 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid; Resolvin E1a; 5S,18R-dihydroxy-6E,8Z,11Z,14Z,16E-eicosapentaenoic acid: Resolvin E2; 7S,8,17R-trihydroxy-docosa-4Z,9E,11E,13Z,15E,19Z-hexaenoic acid: aspirin trigger-type Resolvin D1; 7S,16,17R-trihydroxy-docosa-4Z,8E,10Z,12E,14E,19Z-hexaenoic acid: aspirin trigger-type Resolvin D2; 4S, 11,17R-trihydroxy-docosa-5,7E,9E,13Z,15E,19Z-hexaenoic acid: aspirin trigger-type Re
- the compound of the present invention is a substance which is different from Resolvin/Protectin and is thought not to be a conventionally known substance.
- the present invention provides the following compound.
- P 1 and P 2 are each independently a protective group, a hydrogen atom, alkyl, a hydroxyl group or a substituted hydroxyl group or a combination thereof, when
- R 1 and R 2 are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted branched or non-branched alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted branched or non-branched alkylaryl group, or a combination thereof;
- X is —C(O)OR 3 , —C(O)NR 4 R 5 , —C(O)H, —C(NH)NR 4 R 5 , —C(S)H, —C(S)OR 3 , —C(S)NR 4 R 5 , or —CN;
- R 3 is hydrogen, a protective group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle or a group of the formula: —NR a R b (wherein R a and R b are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
- the present invention provides a compound having the chemical formula:
- P 1 , P 2 , R 1 , R 2 and X are independently as defined above.
- P 1 and P 2 are each a hydrogen atom
- R 1 and R 2 are each independently a methyl group or a hydrogen atom or a combination thereof
- X is carboxylic acid or a carboxylic acid ester.
- X can be carboxylic acid, ester, amide, thiocarbamate, carbamate, thioester, thiocarboxamide, or nitrile.
- X is carboxylic acid, a carboxylic acid ester, or pharmaceutically acceptable carboxylate.
- the present invention provides a compound having the chemical formula:
- P 1 , P 2 , R 1 , R 2 and X are each independently as defined above.
- P 1 and P 2 are each a hydrogen atom
- R 1 and R 2 are each independently a methyl group or a hydrogen atom or a combination thereof
- X is carboxylic acid or a carboxylic acid ester.
- X can be carboxylic acid, ester, amide, thiocarbamate, carbamate, thioester, thiocarboxamide, or nitrile.
- X is carboxylic acid, a carboxylic acid ester, or pharmaceutically acceptable carboxylate.
- the present invention provides a compound having the chemical formula:
- P 1 , P 2 , R 1 , R 2 and X are each independently as defined above.
- P 1 and P 2 are each a hydrogen atom
- R 1 and R 2 are each independently a methyl group or a hydrogen atom or a combination thereof
- X is carboxylic acid or a carboxylic acid ester.
- X can be carboxylic acid, ester, amide, thiocarbamate, carbamate, thioester, thiocarboxamide, or nitrile.
- X is carboxylic acid, a carboxylic acid ester, or pharmaceutically acceptable carboxylate.
- the present invention provides a compound having the chemical formula:
- P 1 , P 2 , R 1 , R 2 and X are each independently as defined above.
- P 1 and P 2 are each a hydrogen atom
- R 1 and R 2 are each independently a methyl group or a hydrogen atom or a combination thereof
- X is carboxylic acid or a carboxylic acid ester.
- X can be carboxylic acid, ester, amide, thiocarbamate, carbamate, thioester, thiocarboxamide, or nitrile.
- X is carboxylic acid, a carboxylic acid ester, or pharmaceutically acceptable carboxylate.
- the present invention provides a compound having the chemical formula:
- P 1 , P 2 , R 1 , R 2 and X are each independently as defined above.
- P 1 and P 2 are each a hydrogen atom
- R 1 and R 2 are each independently a methyl group or a hydrogen atom or a combination thereof
- X is carboxylic acid or a carboxylic acid ester.
- X can be carboxylic acid, ester, amide, thiocarbamate, carbamate, thioester, thiocarboxamide, or nitrile.
- X is carboxylic acid, a carboxylic acid ester, or pharmaceutically acceptable carboxylate.
- the present invention provides a compound having the chemical formula:
- P 1 , P 2 , R 1 , R 2 and X are each independently as defined above.
- P 1 and P 2 are each a hydrogen atom
- R 1 and R 2 are each independently a methyl group or a hydrogen atom or a combination thereof
- X is carboxylic acid or a carboxylic acid ester.
- X can be carboxylic acid, ester, amide, thiocarbamate, carbamate, thioester, thiocarboxamide, or nitrile.
- X is carboxylic acid, a carboxylic acid ester, or pharmaceutically acceptable carboxylate.
- the present invention provides a compound having the chemical formula:
- P 1 , P 2 , R 1 , R 2 and X are each independently as defined above.
- P 1 and P 2 are each a hydrogen atom
- R 1 and R 2 are each independently a methyl group or a hydrogen atom or combination thereof
- X is carboxylic acid or a carboxylic acid ester.
- X can be carboxylic acid, ester, amide, thiocarbamate, carbamate, thioester, thiocarboxamide, or nitrile.
- X is carboxylic acid, a carboxylic acid ester, or pharmaceutically acceptable carboxylate.
- the present invention provides a compound having the chemical formula:
- P 1 , P 2 , R 1 , R 2 and X are each independently as defined above.
- P 1 and P 2 are each a hydrogen atom
- R 1 and R 2 are each independently a methyl group or a hydrogen atom or a combination thereof
- X is carboxylic acid or a carboxylic acid ester.
- X can be carboxylic acid, ester, amide, thiocarbamate, carbamate, thioester, thiocarboxamide, or nitrile.
- X is carboxylic acid, a carboxylic acid ester, or pharmaceutically acceptable carboxylate.
- EPA eicosapentaenoic acid
- DHA docosahexaenoic acid
- 12/15LOX and 8-LOX which have not been conventionally known, and can be said to be an entirely novel compound group in that they belong to other series metabolites which are different from metabolites such as known resolvins and protectins.
- a compound when R 1 , R 2 , P 1 and P 2 are each a hydrogen atom and Z is carboxylic acid, a compound may be either isolated, and/or purified.
- the purity of such a compound based on analysis measurement using GC, MS, or 1 H NMR, is a purity of at least 80%, particularly, a purity of at least about 90%, more particularly, a purity of at least 95%, and more preferably, a purity of at least about 99%. This applies in all isolated compounds and/or purified compounds, throughout the present specification.
- the present invention can be expressed as follows.
- P 1 and P 2 are each independently a protective group, a hydrogen atom, alkyl, a hydroxyl group or a substituted hydroxyl group or a combination thereof, when
- R 1 and R 2 are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted branched or non-branched alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted branched or non-branched alkylaryl group or a combination thereof;
- X is —C(O)ORd, —C(O)NRcRc, —C(O)H, —C(NH)NRcRc, —C(S)H, —C(S)ORd, —C(S)NRcRc, or —CN;
- each Ra when present, is independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10)aryl, phenyl, (C6-C16)arylalkyl, benzyl, 2- to 6-membered heteroalkyl, 3- to 8-membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4- to 11-membered cycloheteroalkylalkyl, 5- to 10-membered heteroaryl and 6- to 16-membered heteroarylalkyl;
- each Rb when present, is a suitable group independently selected from the group consisting of ⁇ O, —ORd, (C1-C3)haloalkyloxy, —OCF 3 , ⁇ S, —SRd, ⁇ NRd, —NRcRc, halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ⁇ N 2 , —N 3 , —S(O)Rd, —S(O) 2 Rd, —S(O) 2 ORd, —S(O)NRcRc, —S(O) 2 NRcRc, —OS(O)Rd, —OS(O) 2 Rd, —OS(O) 2 ORd, —OS(O) 2 NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc,
- each Rc when present, is independently a protective group or Ra, or alternatively, each Rc may be taken together with a nitrogen atom to which it binds to form 5- to 8-membered cycloheteroalkyl or heteroaryl, and these may optionally comprise one or more same or different further heteroatoms, and may be optionally substituted with one or more same or different Ra groups or suitable Rb groups;
- each n when present, is independently an integer of 0 to 3;
- each Rd when present, is independently a protective group or Ra.
- X is carboxylic acid, ester, pharmaceutically acceptable carboxylate, or a prodrug thereof.
- X is a pharmaceutically acceptable salt of carboxylic acid and, particularly, is an ammonium salt, or forms a prodrug.
- each may independently have R configuration or S configuration or R/S configuration.
- P 1 and P 2 when present, are each independently a hydrogen atom, and X is carboxylic acid or ester.
- one or more of P 1 and P 2 are a hydrogen atom, and X is carboxylic acid or ester.
- R 1 and R 2 when present, are each independently a lower alkyl group such as methyl, ethyl or propyl, and can be halogenated like trifluoromethyl. In one embodiment, at least one of R 1 and R 2 , when present, is not a hydrogen atom.
- X is carboxylic acid, and one or more of P 1 and P 2 are a hydrogen atom.
- P 1 and P 2 are each independently a hydrogen atom, and X is a carboxyl ester. In another embodiment, P 1 and P 2 are each independently a hydrogen atom, and X is carboxylic acid. In another embodiment, P 1 and P 2 are each independently a hydrogen atom, and X is not carboxylic acid.
- the compound described in the present specification is isolated and/or purified and, particularly, a compound in which P 1 and P 2 are each independently a hydrogen atom, and X is carboxylic acid is isolated and/or purified.
- the compound of the present invention is useful for treating a disease which can be treated or prevented by suppression of neutrophil, for example, an inflammatory disease.
- a disease which can be treated or prevented by suppression of neutrophil for example, an inflammatory disease.
- Such utility is variously present in addition to an inflammatory disease, and those described elsewhere in the present specification are exemplified.
- the present invention provides the following compound or a pharmaceutically acceptable salt or solvate thereof:
- the compound described in the present specification has anti-inflammatory activity as recognized by down regulation of neutrophil infiltration in a peritonitis model.
- X found in the compound of the present invention can be changed from one particular part to another part by a person skilled in the art.
- one or more groups can necessitate protection. This is also within a range of a person skilled in the art.
- a carboxylic acid ester can be converted into an amide by treatment using an amine. Such interconversion is known in the art.
- hydroxyl stereochemistry
- this term means to include a protected hydroxyl group and a free hydroxyl group.
- the C-17 position has R configuration.
- the C-17 position has S configuration.
- a particular embodiment of the present invention has R configuration at the C-18 position.
- the compound of the present invention can be protected with a variety of protective groups such as those known in the art.
- a person skilled in the art can easily determine which protective group can be useful for protecting a hydroxyl group using procedures etc. described in Green and Wuts, “Protecting Groups in Organic Synthesis”, John Wiley and Sons, Chapters 5 and 7, 1991, and the present specification.
- each of the above-identified compounds can take a variety of forms of isomers. Particularly, it is to be understood that one or more chiral centers are present in the compound of the present invention. It is to be understood that the present invention includes all stereochemistry types of each compound, for example, enantiomers, diastereomers or racemic compounds. When an asymmetric carbon atom is present, more than one steric isomers are possible, and it is intended that all possible isomer types are included in expression of an indicated structure.
- active (R) and (S) isomers may be separated using a conventional technique known to a person skilled in the art. It is intended that the present invention includes possible diastereomers as well as racemic compounds and optically resolved isomers.
- the compound of the present invention comprises an acetylenic and/or ethylenic unsaturated site.
- steric configuration chemistry can be any of cis or trans (Z or E), and expression throughout the present specification does not mean limitation. The expression is generally presented based on steric configuration chemistry of an associated DHA or EPA compound, and is not limited by a theory, but is thought to have the same steric configuration chemistry.
- a bond between carbons is simplified, particularly, in order to show a manner of finally arranging a bond to each other.
- the acetylene part of resolvin actually comprises about 180° geometry, but it is to be understood that, in order to assist understanding of a relationship between synthesis, and a final product and a starting substance, in such an angle, extreme expression is used in order to assist understanding.
- the present invention also includes a compound which can generate one or more kinds of products by hydrogenation of the acetylene part. It is intended that all possible products are included in the present specification.
- hydrogenation of the diacetylenic compound of the present invention can produce up to eight kinds of products (when hydrogenation of both acetylene parts are completed (it can be monitored by a known method), four kinds of diene products, that is, cis, cis; cis, trans; trans, cis; trans, trans), and four kinds of monoacetylene-monoacetylene products (cis or trans “monoene”-acetylene; acetylene-cis or trans “monoene”). All the products can be separated and identified by HPLC, GC, MS, NMR or IR.
- a technique known in the art can be used for converting the carboxylic acid/ester functional group of the compound of the present invention into carboxamide, thioester, nitrile, carbamate or thiocarbamate, and is incorporated in the present specification.
- a suitable part such as an amide can be further substituted as known in the art.
- the compound of the present invention is synthesized by a general organic chemistry procedure, or can be produced by acting an enzyme such as lipoxygenase of 12/15-LOX etc. on 18-HEPE or 20-HDoHE etc. present relatively abundantly as a precursor.
- the present invention provides a method of producing the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof.
- This method includes the steps of A) contacting eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), or 18-hydroxy eicosapentaenoic acid (18-HEPE) or 20-hydroxy docosahexaenoic acid (HDoHE) with 8-lipoxygenase (e.g., mouse recombinant 8-lipoxygenase (8-LOX)), 12-lipoxygenase (12-LOX) (e.g., platelet-type 12-LOX), 12/15-lipoxygenase (12/15-LOX) (e.g., lymphocyte-type 12/15-LOX), soybean lipoxygenase, or eosinophil or an extract thereof to obtain an enzyme metabolite; and B) reducing or oxidizing the enzyme metabolite as necessary, introducing a
- Eosinophil may be used as it is, or an extract thereof may be used as far as objective enzyme activity is seen. It can be said that it is unexpected that 10,20-HDoPE is produced using 8-LOX.
- a desired oxidized body can be obtained by, subsequently to A) step, carrying out the steps of B′) contacting the enzyme metabolite obtained in A) step, after purification or without purification, with at least one selected from the group consisting of 8-lipoxygenase (8-LOX), 12-lipoxygenase (12-LOX), 12/15-lipoxygenase (12/15-LOX), soybean lipoxygenase (sLOX) and eosinophil or an extract thereof to obtain a secondary enzyme metabolite; as well as C′) reducing or oxidizing the secondary enzyme metabolite as necessary, introducing a substituent as necessary, and separating or purifying the objective compound or a pharmaceutically acceptable salt or solvate thereof as necessary; as well as repeating these B′) and C′) steps as necessary.
- 8-LOX 8-lipoxygenase
- 12-LOX 12-lipoxygenase
- 12/15-lipoxygenase 12/15-LOX
- B′) step since a plurality of peroxidized bodies can be obtained in A) step, they can be further oxidized by contacting them with the same enzyme or another enzyme again while they are individually separated (purified), or they are not subjected to purification.
- purification used herein the method described in the present specification is exemplified, and examples thereof include, but are not limited to, HPLC, and it is understood that a degree of separation or purification can be appropriately adjusted.
- an exemplary method includes a method comprising the steps of producing 12-hydroperoxy eicosapentaenoic acid (12-HpEPE) or 14-hydroperoxy docosahexaenoic acid (HpDoHE) using 12-LOX as necessary and, thereafter, A) contacting 12-hydroperoxy eicosapentaenoic acid (12-HpEPE) or 14-hydroperoxy docosahexaenoic acid (HpDoHE) with soybean lipoxygenase to obtain an enzyme metabolite; and B) reducing or oxidizing the enzyme metabolite as necessary, introducing a substituent as necessary, and separating or purifying the objective compound or a pharmaceutically acceptable salt or solvate thereof as necessary ( FIG. 9A and FIG. 9B ).
- the compound of the present invention can be produced using the following compounds:
- 18-HEPE and 20-HDoPE are both metabolites in which just the ⁇ 3 site of ⁇ 3 PUFA has been oxidized.
- Examples of the enzyme used in the method of production of the present invention include 8-lipoxygenase (e.g., mouse recombinant 8-lipoxygenase (8-LOX)), 12-lipoxygenase (12-LOX) (e.g., platelet-type 12-LOX), 12/15-lipoxygenase (12/15-LOX) (e.g., lymphocyte-12/15-LOX), soybean lipoxygenase, and an enzyme obtained from eosinophil, it is understood that a suitable enzyme can be appropriately utilized while the substrate specificity thereof is taken into consideration.
- 8-lipoxygenase e.g., mouse recombinant 8-lipoxygenase (8-LOX)
- 12-lipoxygenase (12-LOX) e.g., platelet-type 12-LOX
- 12/15-lipoxygenase (12/15-LOX) e.g., lymphocyte-12/15-LOX
- soybean lipoxygenase e.g.,
- precursor materials 18-HEPE and 20-HDoPE
- commercially available substances available from Cayman Inc.
- they can be obtained by chemical synthesis or extraction from a living body.
- the method or technique of purification, separation or isolation used in the present specification when necessary, includes column chromatography, high performance liquid chromatography (HPLC), gas chromatography (GC), crystallization, and distillation. Characterization can be performed by such as ultraviolet (UV) analysis, mass analysis (MS), MS/MS, GC/MS, or nuclear magnetic resonance (NMR). A person skilled in the art can utilize various methods for preparing, isolating and characterizing these novel compounds, based on the teaching of the present specification.
- the compound of the present invention can be produced by a method of introducing these substituents into a precursor, and performing an enzyme reaction using a technique known in the art, or a method of producing a compound in which each is hydrogen by the procedure described in the present specification, and thereafter introducing a substituent, or a combination thereof.
- a technique the known technique of producing a derivative in resolvin/protectin can be applied.
- a compound in which P 1 and P 2 are other than hydrogen can be produced by producing a compound in which P 1 and P 2 are hydrogen and, thereafter, substituting the hydroxyl of the compound with an alkyl group or a variety of protective groups (e.g., those known in the art).
- protective groups e.g., those known in the art.
- a person skilled in the art can easily determine which protective group can be useful for protecting these hydroxyl groups.
- a standard method is known in the art, and is sufficiently described in documents.
- substitution with an alkyl group and substitution with a suitable protective group are carried out, and easily selected by a person skilled in the art, and a content described in Green and Wuts, “Protecting Groups in Organic Synthesis”, John Wiley and Sons, Chapters 5 and 7, 1991 (the teaching content of which is incorporated in the present specification as reference) can be taken into consideration.
- the protective group include methyl and ethyl esters, TMS and TIPPS groups, an acetic acid ester or a propionic acid ester, and glycol ether (e.g., ethylene glycol and propylene glycol derivatives).
- P 1 and P 2 are each a hydroxyl group or a substituted hydroxyl group, that is, regarding a peroxide body, a product obtained by an enzyme reaction may be separated, or in the case of a substituted hydroxyl group, a peroxide body may be further substituted with a substituent such as an alkyl group, or a protective group using the known technique.
- a peroxide body may be further substituted with a substituent such as an alkyl group, or a protective group using the known technique.
- the known technique of producing a derivative in resolvin/protectin can be applied.
- R 1 and R 2 are each a halogen atom, a substituted or unsubstituted branched or non-branched alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted branched or non-branched alkylaryl group or a combination thereof
- the compound of the present invention can be produced by a method of introducing these substituents into a precursor, and performing an enzyme reaction using a technique known in the art, or a method of producing a compound in which each is hydrogen by the procedure described in the present specification, and thereafter introducing a substituent, or a combination thereof.
- the known technique of producing a derivative in resolvin/protectin can be applied.
- R 1 and R 2 are other than hydrogen, that is, use of “R protecting chemistry” is not necessarily required in an adjacent diol in the compound of the present invention.
- the adjacent diol is not easily oxidized and, for this reason, generally, such protection is not required by substitution of a hydrogen atom adjacent to the oxygen atom of a hydroxyl group. Therefore, it is generally deemed that such protection is not necessary, and it is possible to prepare a compound in which the hydroxyl group of an adjacent diol “can be protected” independently by substitution of a hydrogen atom adjacent to the oxygen atom of a hydroxyl group, using the aforementioned substituent as a protective group.
- the known technique of producing a derivative in resolvin/protectin can be applied.
- R 1 and R 2 groups for example, a hydroxyl group is oxidized by Pfitzner-Moffatt oxidation, Swern oxidation, Jones oxidation etc., to obtain a ketone, and a substituent such as alkyl, aryl, or alkylaryl can be introduced into R 1 and R 2 together with reduction into an alcohol, by Grignard reaction, Barbier coupling reaction, Kagan-Molander reaction in the presence of diiodosamarium, etc. and, if necessary, P 1 , P 2 , etc. can be further introduced thereinto.
- the known technique of producing a derivative in resolvin/protectin can be applied.
- the following synthesis route illustrates a method of preparing the objective compound of the present invention.
- a preparation product does not intend limitation, but more traditionally, works as another means for preparing the compound of the present invention in line with implementation, and should be deemed as complementation for the biological synthesis.
- the compound of the present invention can be also synthesized by an organic synthesis method.
- the present invention provides a neutrophil suppressing agent comprising the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof.
- the present invention provides a method of treating or preventing an inflammatory disease comprising the step of administering the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof to a subject in need of the treatment or the prevention.
- the present invention relates to use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for producing a medicament, in the method of treating or preventing an inflammatory disease.
- the present invention relates to use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for producing a medicament for treating or preventing a disease, a disorder or a state associated with neutrophil.
- drug neutril suppressing agent etc.
- treating method preventing method
- production of a medicament for treatment or prevention there are the following embodiments. They will be described in turn below.
- the present invention can, for example, prevent infiltration into a tissue of, and activation of neutrophil at acute inflammation.
- Such preventing ability is useful for preventing infiltration into a tissue of, and activation of neutrophil found in ischemic reperfusion disorder, cerebral apoplexy, cardiac infarction, acute nephritis, etc. Therefore, since the present invention strongly suppresses infiltration into a tissue of, and activation of neutrophil at a very low dose, it is understood that it is useful as having an effect thereof as a therapeutic.
- disease, disorder or symptom associated with neutrophil refers to a disease, a disorder or a symptom which is improved by inhibiting neutrophil.
- a disease state or symptom is described throughout the present specification, the entire of which is incorporated in the present specification.
- the currently unknown state associated with neutrophil regulation, which may be found in the future, is included in the present invention, because characterization as a state associated with neutrophil regulation can be easily determined by a person skilled in the art.
- the present invention also relates to a method of treating, remitting or curing a disease state or a symptom associated with inflammation.
- a disease which is a target of the present invention includes the followings.
- Many gastrointestinal inflammatory disorders of an alimentary system mouth, stomach, esophagus, small intestine and large intestine
- stomatitis a disease which is a target of the present invention
- inflammatory intestinal diseases such as ulcerative colitis and Crohn disease, infectious enterocolitis (viral, bacterial, parasitic organismic), antibiotic-associated diarrhea, Clostridium difficile colitis, microscopic or lymphocytic colitis, collagenous colitis, colon polyp and familiar polyp syndrome (e.g., familiar polyposis syndrome, Gardner syndrome), Helicobacter pylori , irritable bowel syndrome, non-specific diarrhea, and intestine cancer
- inflammatory diseases such as inflammatory bowel disease (IBD), colitis which is induced by stimulation from external world (e.g., inflammation of gastrointestine (e.g., colitis) which is caused by therapeutic regimens such as administration of chemotherapy, and radiation therapy, or is associated there
- Inflammation includes acute and chronic inflammatory states.
- Acute inflammation is generally characterized by onset in a short time, and infiltration or inflow of neutrophil.
- Chronic inflammation is generally characterized by onset in a relatively long term (e.g., a few days, a few weeks, a few months, or a few years, and up to a life of a subject) and infiltration or inflow of mononuclear cells.
- Chronic inflammation is also typically characterized by a term of spontaneous recovery and spontaneous development.
- the present invention provides a medicament comprising the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof.
- the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone as it is, but is usually preferably provided as various medical formulations. Those medical formulations can be used in an animal and human.
- a route which is the most effective upon therapy is preferably used, and examples thereof include oral routes and parenteral routes such as intrarectal, intravaginal, intranasal, oral cavity, sublingual, transdermal, subcutaneous, intramuscular, and intravenous.
- the amount of an active ingredient which can be combined with a carrier material for producing a single dosage form is generally an amount of a compound generating a therapeutic effect. Generally, among 100 percent, this amount is in a range of about 1 percent to about 99 percent of an active ingredient, preferably, about 5 percent to about 70 percent, and most preferably, about 10 percent to about 30 percent.
- capsules As an administration form, there are capsules, tablets, pills, granules, powders, syrups, lozenges (preferable base, usually, sucrose and acacia or tragacanth are used), emulsions, suppositories, injectables, etc.
- Liquid preparations such as emulsions and syrups which are suitable for oral administration can be produced employing water, sugars such as sucrose, sorbit, and fructose, glycols such as polyethylene glycol, and propylene glycol, oils such as a sesame oil, an olive oil, and a soybean oil, antiseptics such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor, and peppermint, etc.
- capsules, tablets, powders, granules etc. can be produced by using excipients such as lactose, glucose, sucrose, and mannit, disintegrating agents such as starch, and sodium alginate, lubricants such as magnesium stearate, and talc, binding agents such as polyvinyl alcohol, hydroxypropylcellulose, and gelatin, surfactants such as fatty acid ester, plasticizers such as glycerin, etc.
- excipients such as lactose, glucose, sucrose, and mannit
- disintegrating agents such as starch, and sodium alginate
- lubricants such as magnesium stearate
- talc talc
- binding agents such as polyvinyl alcohol, hydroxypropylcellulose, and gelatin
- surfactants such as fatty acid ester
- plasticizers such as glycerin, etc.
- the preparations may be as solutions or suspensions in an aqueous or non-aqueous liquid, or as oil in water or water in oil liquid emulsions, or as elixirs or syrups, or aromatic tablets (using inactive bases such as gelatin and glycerin, or sucrose and acacia) and/or mouth wash, and each comprises a predetermined amount of the compound of the present invention as an active ingredient.
- the compound of the present invention can also be administered as boluses, electuaries or pastes.
- Formulations suitable for parenteral administration comprised of sterilized aqueous formulations comprising an active compound which is preferably isotonic with blood of a recipient.
- solutions for injection are prepared using carries comprised of salt solutions, glucose solutions or a mixture of an aqueous salt and a glucose solution, etc.
- “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or vehicle, for example, a liquid or solid filler, diluent, excipient, solvent or capsulating material, which is contained upon carriage or transportation of the compound of the present specification into or to a subject so that the carrier conducts the intended performance.
- a pharmaceutically acceptable material for example, a liquid or solid filler, diluent, excipient, solvent or capsulating material, which is contained upon carriage or transportation of the compound of the present specification into or to a subject so that the carrier conducts the intended performance.
- a pharmaceutically acceptable material for example, a liquid or solid filler, diluent, excipient, solvent or capsulating material, which is contained upon carriage or transportation of the compound of the present specification into or to a subject so that the carrier conducts the intended performance.
- such a compound can be carried or transported from one organ or a part of a body to another organ or part of a body.
- Each carrier must be “acceptable” in
- a material which can work as a pharmaceutically acceptable carrier include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose such as carboxymethylcellulose sodium, ethylcellulose and cellulose acetate and derivatives thereof; powdery tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as a peanuts oil, a cottonseed oil, a safflower oil, a sesame oil, an olive oil, a corn oil and a soybean oil; glycols such as propylene glycol, polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; water not containing a pyrogen; isotonic physiological
- the compound of the present invention may comprise one or more acidic functional groups and, therefore, can form a pharmaceutically acceptable salt with a pharmaceutically acceptable base.
- a pharmaceutically acceptable salt or base for example, Berge S. M. et al., “Pharmaceutical Salts”, J. Pharm. Sci, 1977; 66:1-19 ca be referred (this is incorporated in the present specification as reference).
- Local formulations are prepared by dissolving or suspending an active compound in one or more kinds of media, for example, mineral oils, petroleum, and polyhydric alcohols or other bases used in local pharmaceutical formulations.
- Formulations for intraintestinal administration are provided as suppositories by preparation using normal carriers, for example, cacao butter, hydrogenated fat, and hydrogenated fat carboxylic acid.
- auxiliary ingredients selected from glycols, oils, flavors, antiseptics (including antioxidants), excipients, disintegrating agents, lubricants, binding agents, surfactants, plasticizers, etc. exemplified in oral agents can also be added.
- antioxidants examples include water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and ⁇ -tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.
- water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, and sodium sulfite
- oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and ⁇ -tocopherol
- a suitable dose for one day or one time of the compound of the present invention or a pharmaceutically acceptable salt thereof, etc. is an amount of the compound which is an effective minimum dose for generating a therapeutic effect, and it is understood that an effective dose and an administration time of the compound of the present invention or a pharmaceutically acceptable salt thereof, etc. are different depending on an administration form, an age and a weight of a patient, a nature and severity of symptom to be treated, etc.
- an oral administration amount is 0.01 to 1000 mg/person, preferably 5 to 500 mg/person per one day, and it is preferable that as an administration time, the compound is administered once a day or by division.
- a therapeutic or preventive effective amount is, for example, 0.1 to 20 mg/kg weight, and more preferably 1 to 10 mg/kg weight.
- the compound of the present invention at between about 0.01 ⁇ g to 20 ⁇ g, between about 20 ⁇ g to 100 ⁇ g, or between 10 ⁇ g to 200 ⁇ g is administered per 20 g of a subject weight. It should be noted that there is a possibility that the value of an administered dose may vary along with a type and severity of the state to be alleviated.
- a method of preparing these formulations or compositions includes the step of combining the compound of the present invention with a carrier and, optionally, one or more kinds of auxiliary ingredients.
- formulations are prepared by the steps of uniformly and closely combining the compound of the present invention with a liquid carrier, or a finely divided solid carrier, or both of them and, then, molding a product if necessary.
- an active ingredient is mixed with one or more kinds of pharmaceutically acceptable carries, for example, sodium citrate or dipotassium phosphate and/or any of the followings: fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; binding agents such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; humectants such as glycerol; disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, particular silicic acid, and sodium carbonate; solution retardants such as paraffin; absorption accelerating agents such as a quaternary ammonium compound; wetting agents such as cetyl alcohol and monostearic acid glycerol
- a pharmaceutical composition may also comprise buffers.
- the same type of a solid composition may also be utilized as fillers in filled soft and hard gelatin capsules employing an excipient such as lactose or milk sugar, as well as a high-molecular polyethylene glycol.
- Tablets may be prepared by compression and molding with optionally selective one or more kinds of auxiliary ingredients.
- Compressed tablets may be prepared employing binding agents (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inactive diluents, preservatives, disintegrating agents (e.g., starch glycolate sodium or crosslinked carboxymethylcellulose sodium), surface active agents or dispersants.
- Molded tablets may be prepared by molding a mixture of powdery compounds wetted with an inactive liquid diluent using a suitable machine.
- Tablets or other solid dosage forms of the pharmaceutical composition of the present invention may be optionally given or prepared with coatings and shells, for example, enteric coatings and other coatings well-known in the field of medicament formulations. These also may be prepared into formulations employing a variety of proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes and/or microspheres in order to provide delayed release or controlled release of an active ingredient therein, for example, in order to provide a desired release profile.
- compositions may be sterilized, for example, by filtration by passing through a bacterium-retaining filter, or incorporating a sterilizing drug in a type of a sterilizing solid composition which can be dissolved in sterilized water or a certain other sterilized injectable medium immediately before use.
- These compositions may also include optionally an opaquer, or they may be a composition which releases only an active ingredient, or preferentially releases an active ingredient to a particular part of a gastrointestinal tract optionally in a delayed manner.
- an embedding composition which can be used include polymeric substances and waxes.
- An active ingredient when appropriate, can be a microcapsulated type accompanying one or more kinds of the excipients.
- a liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
- the liquid dosage form can include inactive diluents which are generally used in the art, for example, water and other solvents, solubilizers and emulsifying agents, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid ester of sorbitan, and a mixture thereof.
- inactive diluents which are generally used in the art, for example, water and other solvents, solub
- the oral composition of the present invention can also include, in addition to the inactive diluents, adjuvants such as wetting agents, emulsifying agents and suspending agents, sweeteners, perfumes, coloring materials, aromatic agents, and preservatives.
- adjuvants such as wetting agents, emulsifying agents and suspending agents, sweeteners, perfumes, coloring materials, aromatic agents, and preservatives.
- the suspension of the present invention may include, in addition to an active compound of the present invention, suspensions, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and a mixture thereof.
- suspensions for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and a mixture thereof.
- a formulation of the pharmaceutical composition of the present invention may be provided as a suppository for rectal or vaginal administration, and this can be prepared by mixing one or more kinds of suitable non-stimulating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, which are solid at room temperature but are liquid at a body temperature and, therefore, are dissolved in rectum or vaginal cavity, and release an active compound, with at least one compound of the present invention.
- suitable non-stimulating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, which are solid at room temperature but are liquid at a body temperature and, therefore, are dissolved in rectum or vaginal cavity, and release an active compound, with at least one compound of the present invention.
- the formulation of the present invention encompasses also pessaries, tampons, creams, gels, pastes, foams, or spray preparations, including carries which are known in the art to be appropriate for vaginal administration.
- a dosage form for locally or transdermally administering the compound of the present invention includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
- An active compound may be mixed with a pharmaceutically acceptable carrier, and an optional preservative, buffer or aerosol agent which can be necessary under the sterilized condition.
- pastes, creams, and gels may be added excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc dioxide, or a mixture thereof, in addition to an active compound of the present invention.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc dioxide, or a mixture thereof, in addition to an active compound of the present invention.
- Powders and sprays can include, in addition to the compound of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and a polyamide powder, or a mixture of these substances.
- Sprays can further include conventional aerosol agents, such as volatile unsubstituted hydrocarbons such as chlorofluorohydrocarbon as well as butane and propane.
- Transdermal patches have an additional advantage of providing controlled delivery of the compound of the present invention to a body.
- a dosage form can be made by dissolving or dispersing a compound in a suitable medium.
- An absorption potentiating agent can be also used for increasing inflow of a compound crossing a skin.
- a rate of such inflow can be controlled by either of provision of a rate controlling membrane, or dispersion of an active compound in a polymer matrix or a gel.
- the present invention encompasses ophthalmic formulations, ocular ointments, powders or solutions, and such solutions are useful for treating conjunctivitis.
- the pharmaceutical composition of the present invention is used for parenteral administration, includes at least one composition of the present invention combined with a pharmaceutically acceptable sterilized isotonic aqueous solution or non-aqueous solution, a dispersion, a suspension or an emulsion, or a sterilized powder which can be reconstituted into a sterilized injection solution or a dispersion immediately before use, and this may include antioxidants, buffers, bacteriostatic agents, solutes which are isotonic with blood of a recipient who is intended for formulations, or suspensions or thickeners.
- a suitable aqueous and non-aqueous carrier which may be utilized in the pharmaceutical composition of the present invention include water, ethanol, polyol (e.g., glycerol, propylene glycol, and polyethylene glycol), and a suitable mixture thereof, a vegetable oil, for example, an olive oil, and an injectable organic ester, for example, ethyl oleate.
- Suitable flowability can be maintained by use of a coating material such as lecithin, maintenance of a particle size required in the case of dispersion, and use of a surfactant.
- compositions may also include adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersants.
- adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersants.
- Hampering of the action of microorganisms may be guaranteed by inclusion of a variety of antibacterial agents and anti-fungal agents, for example, paraben, chlorobutanol, phenol, and sorbic acid. It can be also desired that an isotonic, for example, a sugar and sodium chloride be contained in the composition.
- prolongation of absorption of an injectable pharmaceutical type can be attained by inclusion of an agent which delays absorption such as aluminum monostearate and gelatin.
- absorption of a drug from subcutaneous or intramuscular injection be delayed.
- This may be attained by using a liquid suspension of a crystalline or amorphous substance having poor water-solubility.
- a rate of absorption of a drug can depend on a rate of its dissociation and, then, can depend on a crystal size and a crystal type.
- delayed absorption of a drug type which has been parenterally administered is attained by dissolving or suspending a drug in an oil vehicle.
- An injectable depo-type can be prepared by forming a microcapsule matrix of a subject compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on a ratio of a drug relative to a polymer, a nature of a utilized particular polymer and a rate of drug release can be controlled. Examples of other biodegradable polymer include poly(orthoester) and poly(anhydride).
- a depo-injectable formulation can be also prepared by inclusion of a drug in a liposome or a microemulsion which is compatible with a body tissue.
- the present invention also provides a packaged medicament including a novel compound described throughout the present specification, for use in treating or preventing a variety of disease states and symptoms.
- prevention refers to no occurrence or at least delaying of a disease, a disorder or a symptom, by any means, before occurrence of the disease, the disorder or the symptom which is a target of the present invention, or making the state where even if a cause itself for a disease, a disorder or a symptom occurs, a disorder does not occur based on the cause.
- treatment refers to arrestment of progression of a disease, a disorder or a symptom which is a target of the present invention, which has been already developed, or improvement in a disease, a disorder or a symptom which is a target of the present invention, whether complete or partial.
- subject refers to an animal to be handled for a disease, a disorder or a symptom which is a target of the present invention.
- An animal to be handled by the present invention may be, for example, birds and mammals.
- such an animal can be a mammal (e.g., monotreme, marsupial, edentate, dermatopteran, chiroptera, carnivore, insectivore, proboscideans, perissodactyl, artiodactyla, tubulidentata, squamata, sirenia, Cetacea, primate, rodent and Lagomorpha).
- Examples of an exemplary subject are not limited to, but include an animal such as cow, pig, horse, chicken, cat, and dog. Further preferably, a small animal such as mouse, rat, rabbit, hamster and guinea pig can be used. Of course, a subject of the present invention includes human, dog, cat, cow, goat and mouse.
- Preparations of the present invention can be given orally, parenterally, locally or rectally. These, of course, are given by a suitable type regarding each administration route. For example, these are administered in tablets or capsules by administration by injection, infusion or inhalation of injections, inhalations, ocular lotions, ointments, suppositories etc.; in lotions or ointments locally; and in suppositories rectally.
- oral administration and “orally administered”, when used in the present specification, usually mean an administration manner other than enteral and local administration by injection and, without limitation, include intravenous, intramuscular, intra-arterial, intrathecal, intravesical, intraorbital, intracardial, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal and sternal injections and infusions.
- phrases “systemic administration”, “systemically administered”, “peripheral administration” and “peripherally administered”, when used in the present specification, mean administration of a compound, a drug or other substance other than direct administration to a central nervous system, in which, as a result, it enters a system of a patient and, therefore, it is subjected to metabolism and other similar process, for example, subcutaneous administration.
- the compound of the present invention can be administered to a human and other animal for treatment, orally, to noses, for example, by spraying, or by an optional suitable route including by powders, ointments or drops including buccals and sublingual formulations, rectally, intravaginally, parenterally, intracisternally, and locally.
- the compound of the present invention which may be used in a suitable hydrate type, and/or the pharmaceutical composition of the present invention can be formulated into a pharmaceutically acceptable dosage form by the conventional method known to a person skilled in the art.
- An actual drug administration level of an active ingredient in the pharmaceutical composition of the present invention can vary so that an amount of an active ingredient effective for attaining a desired therapeutic response to a particular patient, a composition, and an administration manner is obtained without accompanying toxicity to a patient.
- a selected drug administration level depends on a variety of factors including activity of a particular compound of the present invention to be utilized, an ester, a salt or an amide thereof, a route of administration, a time of administration, a rate of excretion of a particular compound to be utilized, a term of treatment, other drug, compound and/or substance to be used in combination with a particular compound to be utilized, an age, a sex, a weight, the state, general health state, and the previous medical history of a patient to be treated, as well as the similar factors well-known in the medical field.
- a physician or a veterinarian having normal skill in the art can easily determine and formulate a required effective amount of the pharmaceutical composition. For example, a physician or a veterinarian can initiate administration of the compound of the present invention in the pharmaceutical composition at a level less than that required for attaining the desired therapeutic effect, and gradually increase an administration amount until the desired effect is attained.
- a suitable one day dose of the compound of the present invention is an amount of a compound which is an effective minimum dose for generating the therapeutic effect. Such an effective dose generally depends on the aforementioned factors.
- an intravenous dose and a subcutaneous dose of the compound of the present invention for a patient, when used for the indicated analgesic effect are in a range of about 0.0001 to about 100 mg/kg weight per one day, more preferably, about 0.01 to about 50 mg/kg weight per one day, and further more preferably, about 0.1 to about 40 mg/kg weight per one day.
- the compound of the present invention in a range from about 0.01 ⁇ g to 20 ⁇ g, from about 20 ⁇ g to 100 ⁇ g, or from 10 ⁇ g to 200 ⁇ g is administered per 20 g of a weight of a subject.
- an effective one day dose of an active compound is separately administered, optionally, as 2, 3, 4, 5, 6 or more divided doses at a suitable interval throughout one day in a unit dosage form.
- the pharmaceutical composition of the present invention includes a “therapeutically effective amount” or “preventively effective amount” of at least one compound of the present invention.
- the “therapeutically effect amount” refers to an effective amount at an administration amount and a time necessary for attaining the desired therapeutic result, for example, decrease or prevention of the effect associated with a variety of disease states or symptoms.
- a therapeutically effective amount of the compound of the present invention can vary according to factors such as a disease state, an age, a sex and a weight of an individual, and the ability of the therapeutic compound which induces the desired effect in an individual.
- the therapeutically effective amount also increases the therapeutically advantageous effect for arbitrary toxicity or harmful influence of a therapeutic.
- the “preventively effective amount” refers to an effective amount at an administration amount and a time necessary for attaining the desired preventive result. Typically, since a preventive dose is used before a disease or at an initial stage thereof, a preventive effective amount is smaller than a therapeutically effective amount.
- a regimen can be adjusted for providing an optimal desired response (e.g., therapeutic response or preventive response). For example, a single time bolus can be administered, some divided doses can be administered over a time, or this dose can be proportionally decreased or increased as shown by the requirement of the therapeutic state. For easiness of administration and uniformity of drug administration, it is particularly advantageous to formulate a parenteral composition in a unit dosage form.
- a unit dosage form when used in the present specification, refers to a physically discrete unit suitable as a unit administration amount for a mammal subject to be treated; each unit contains a predetermined amount of an active ingredient calculated to generate the desired effect in cooperation with a required pharmaceutical carrier.
- a unit dosage form of the present invention Details of a unit dosage form of the present invention are determined by (a) the peculiar properties of the compound of the present invention and the particular therapeutic or preventive effect which is attained, as well as (b) inherent limitation in the art of constitution of such an active compound in order to treat sensitivity in an individual, and directly depend on them.
- An illustrative non-limiting range of a therapeutically or preventively effective amount of the compound of the present invention is 0.1 to 20 mg/kg, and more preferably 1 to 10 mg/kg. It should be noted that there is a possibility that a value of an administration amount varies with a type and severity of the state to be alleviated. It is to be further understood that, for an arbitrarily particular subject, a particular administration amount • an administration frequency etc. should be adjusted with time according to necessity of an individual, as well as professional determination of a person who manages a composition or supervises administration of a composition, and an administration amount range shown in the present specification is only illustrative, and does not intend to limit the scope and implementation of the present invention.
- the compound of the present invention can be administered to lung in an aerosol type having a respirable sized particle (diameter of less than about 10 ⁇ m).
- This aerosol preparation can be provided as a liquid or a dry powder.
- a particle can be prepared as a suspension at a respiratory size and, then, can be incorporated into a suspension formulation including an aerosol agent.
- a formulation can be prepared in a solution type in order to avoid a fear regarding a suitable particle size in a formulation.
- a solution formulation should be dispersed in a manner for producing particles or liquid droplets of a respiratory size.
- the aerosol formulation is filled into an aerosol canister provided with a metered-dose valve.
- the formulation is dispensed via an actuator adapted to direct a dose from the valve to a subject.
- the formulation of the present invention can be prepared by combining (i) a sufficient amount of at least one compound for providing a plurality of therapeutically effective doses; (ii) addition of water at an effective amount for stabilizing respective formulations; (iii) a sufficient amount of an aerosol agent for spraying a plurality of doses from an aerosol canister; and (iv) an optional further selective ingredient, for example, ethanol as a co-solvent; and dispersing ingredients.
- Ingredients can be dispersed by shaking using the conventional mixer or homogenizer, or by ultrasound energy.
- a bulk formulation can be moved to smaller individual aerosol vials by using a method of moving from a valve to a valve by filling a pressure, or by using the conventional cold filling method.
- a stabilizer used is soluble in an aerosol agent in a suspension aerosol formulation.
- a stabilizer which is not well soluble can be coated on a suitable amount of a drug particle and, then, the coated particle can be incorporated into a formulation as described above.
- the common valve preferably an aerosol canister provided with a metered-dose valve
- a metered-dose valve can be also used.
- the conventional neoprene and buna valve rubbers used in a metered-dose valve for delivering the conventional CFC formulation can be used with a formulation including HFC-134a or HFC-227.
- the formulation of the present invention can be contained in the coated or not coated, anodized or not anodized conventional aerosol canister, for example, that of aluminum, glass, stainless steel, polyethylene terephthalate.
- the formulation of the present invention can be delivered to a respiratory tract and/or lung by oral inhalation, in order to result in bronchodilation or treat the state sensitive to treatment by inhalation, for example, asthma, and chronic obstructive lung disease, as described throughout the present specification.
- the formulation of the present invention can be also delivered by nasal inhalation as known in the art, in order to treat or prevent the aspiration state as referred throughout the present specification.
- the present invention also includes a packaging material, and a product including a formulation of the compound of the present invention contained in the packaging material.
- This formulation includes at least one compound of the present invention, and the packaging material includes a label or a package insert showing that the formulation can be administered to a subject at a constant amount, at a constant frequency, and for an effective term for treating or preventing one or more kinds of the states described in the present specification in order to treat such states.
- states are referred throughout the present specification, and are incorporated into the present specification by reference.
- the compound described in the present specification can be utilized.
- the present invention features a packaging material, and a product including at least one compound of the present invention contained in the packaging material.
- the packaging material includes a label or a manual showing that the formulation can be administered to a subject in order to treat or prevent a symptom associated with a disease discussed throughout the present specification.
- the medicament of the present invention is useful in treatment or prevention of a disease, a disorder, a state or the like which is not limited to, but includes the following: lung diseases such as lung distress syndrome, adult respiratory distress syndrome, and chronic obstructive pulmonary syndrome (COPD); ischemic diseases such as ischemic cardiac disease, ischemic renal disease, ischemic brain disease, and ischemic liver disease; many gastrointestinal inflammatory disorders of an alimentary system (mouth, stomach, esophagus, small intestine and large intestine), for example, stomatitis, periodontal disease, esophagitis, gastritis, inflammatory intestinal disease such as ulcerative colitis and Crohn's disease, infectious enterocolitis (viral, bacterial, parasitic organismic), antibiotic-associated diarrhea, Clostridium difficile colitis, microscopic or lymphocytic colitis, collagenous colitis, colon polyp and familiar polyp syndrome (e.g., familiar polyposis syndrome and Gardner syndrome
- lung diseases such as lung distress syndrome, adult respiratory
- the pharmaceutical composition of the present invention is an agent for treating and/or preventing diseases such as encephalitis, myelitis and encephalomyelitis, meningitis, inflammatory multiple neuropathy, neuritis, dacryoadenitis, orbital inflammation, conjunctivitis (allergic conjunctivitis, spring keratoconjuctivitis etc.), keratitis, chorioretinal scar, endophthalmitis, retrobulbar neuritis, retinopathy, glaucoma, cellulitis, external otitis, perichondritis, tympanitis, salpingitis, mastoiditis, myringitis, labyrinthitis, pulpitis,
- diseases such as encephalitis, myelitis and encephalomyelitis, meningitis, inflammatory multiple neuropathy, neuritis, dacryoadenitis, orbital inflammation, conjunctivitis (allergic conjunctivitis,
- the present invention also relates to a method of treating or preventing a gastrointestinal disease or the state in a subject, by administration by joint use with other anti-inflammatory agent, for example, other drug such as a steroid agent or NSAID (aspirin, ibuprofen etc.).
- other drug such as a steroid agent or NSAID (aspirin, ibuprofen etc.).
- NSAID aspirin, ibuprofen etc.
- the present invention provides a method of analyzing the present invention. This can be directed for assaying these compounds with a human body fluid (blood, urine, breast milk), or a biopsy material, as a therapeutic marker for assessing a n ⁇ 3 state level effective as an index for developing therapeutic base for anti-inflammation.
- a human body fluid blood, urine, breast milk
- a biopsy material as a therapeutic marker for assessing a n ⁇ 3 state level effective as an index for developing therapeutic base for anti-inflammation.
- This includes LC-MS-MS and GC-MS properties, and this can also result in far easy development for handling an ELISA assay for monitoring these novel products.
- the present invention provides a method of analyzing the compound of the present invention or a PUFA metabolite, including the following liquid chromatography condition:
- Short Protocols in Molecular Biology A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Ausubel, F. M. (1995). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Innis, M. A. et al. (1995). PCR Strategies, Academic Press; Ausubel, F. M. (1999). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Wiley, and annual updates; Sninsky, J. J. et al. (1999).
- MRM is a procedure which can analyze an objective metabolite selectively and at a high sensitivity using MS/MS ( FIG. 1A ).
- MS/MS of a metabolite of PUFA for example, an oxide causes fragmentation at a carbon-carbon bond before and after its hydroxyl group. Then, a MS/MS value characteristic in a structure of the metabolite is detected.
- a procedure of selectively detecting only a substance having a combination of parent MS value/child MS value letting a MS value derived from a molecular weight of a certain metabolite (due to a negative ion mode, in the case of a PUFA metabolite, a MS value at extraction and ionization of a proton, molecular weight-1) to be a parent MS value (M ⁇ ), and a MS/MS value characteristic in a structure of the metabolite to be a child MS value (A ⁇ ) is MRM.
- a pre-set parent MS value is first selectively detected with Q1.
- an elution time of a metabolite upon separation by LC is 3 seconds or longer, detection of the metabolite is possible. Since an actual elution time is around 10 and a few seconds, in principle, 300 or more kinds of metabolites can be detected. However, when performance of a detection around peak top is also taken into consideration, up to about one hundred and few tens kinds of metabolites can be analyzed at once while quantitative property is also retained. Further, by combining a separation system using LC, information of a retention time specific for each metabolite is obtained and, from information of them, at once quantitative analysis of an objective metabolite group at a high sensitivity can be performed.
- MRM multiple reaction monitoring
- PGE 2 20-hydroxy-PGE 2 , PGD 2 , PGF 2 ⁇ , 6-keto-PGF 1 ⁇ , 15-deoxy- ⁇ 12,14 -PGJ 2 , LxA 4 , LTB 4 , 20-hydroxy-LTB 4 , LTC 4 , LTD 4 , TxB 2 , 5-HETE, 5,6-EET, 8-HETE, 8,9-EET, 12-HETE, 11,12-EET, 15-HETE, 14,15-EET, 16-HETE, 17-HETE, 20-HETE, 5,15-diHETE, 8,15-diHETE, 14,15-diHETE, 17,18-diHETE, 5-oxo-ETE, 15-oxo-ETE, LTB 5 : Biomol, RvE2 (gifted from the present department organic reaction chemistry laboratory), PGE 3 , PGD 3 , RvE1,5-HEPE, 8-HEPE, 12-HEPE, 15-HEPE, 14,15-EpETE, 18
- a MS/MS value characteristic in a structure of the compound was selected from measured MS/MS values, respectively, and measurement was performed by varying a cone voltage and a collision energy, thereby, the condition under which the MS/MS value was detected at the best sensitivity was determined.
- HPLC Waters
- B liquid: acetonitrile/methanol 4/1, a ratio and a flow rate were regulated every hour, and the condition under which a mixture of standard compounds was eluted at a good separation degree within 30 minutes was determined.
- Final LC condition is as follows:
- a MRM channel specific for each compound was prepared.
- a channel was prepared hypothetically, with reference to a MS/MS value presumed from a structure, and a cone voltage and a collision energy of a metabolite having a similar structure.
- PUFA metabolites are basically such that oxygen (hydroxyl group) is added to a variety of positions of a carbon chain of PUFA, and are structurally very similar, separation is difficult.
- acetonitrile, methanol and water were mixed at a variety of amount ratios, and a flow rate was optimized, a system which separates PUFA metabolites very well in 45 minutes was established.
- a HEPE standard mixture was separated by LC, MRM analysis was performed, and a chromatogram of a channel specific for each metabolite is shown.
- 18-HEPE and 17,18-EpETE are the same in a fragment of structurally specific MS/MS, both of them are detected in one channel, but by establishing a system of LC having the high separation ability, each of them could be discriminated due to difference in a retention time.
- PBS Phosphate buffered physiological saline
- NaCl sodium chloride
- KCl 2.7 mM potassium chloride
- HESS Hanks' Balanced Salt Solution
- DMSO dimethyl sulfoxide
- 18-HEPE Cayman.
- Zymosan A was suspended in a physiological saline at 1 mg/mL, and the suspension was warmed at 37° C. for 30 minutes. This was intraperitoneally administered to a mouse at 1 mL. After 4 hours and 48 hours, the mouse was slaughtered, and 5 mL of PBS was injected into an abdominal cavity. After peritoneum was massaged 100 times, a total amount of an intra-abdominal fluid was recovered into a tube. After counting of cells, centrifugation was performed at 1200 rpm and 4° C. for 5 minutes, HBSS was added to cells (ppt), and 900 ⁇ L was transferred into a 50 mL tube (5 ⁇ 10 6 cells/tube). The tube containing cells was pre-incubated at 37° C.
- 18-HEPE was first taken into a 1.5 mL tube, and a solvent was vaporized with nitrogen, to complete dryness. HBSS was added thereto, and this was ultrasound-treated to dissolve it (200 ⁇ M). A23187 was diluted with HBSS to 40 ⁇ M. Each 50 ⁇ L of the above-adjusted 18-HEPE and A23187 were added to the tube containing cells, and this was incubated at 37° C. for 30 minutes while a lid was opened partially (18-HEPE was 10 ⁇ M, A23187 was 2 ⁇ M final concentration).
- 18-HEPE was incubated with PEC, and analysis by MRM was performed.
- RvE1 and RvE2 known as an anti-inflammatory mediator
- 18-HEPE-dependant peaks were recognized in some MRM channels ( FIG. 2A ). These peaks are thought to be 8,18-diHEPE, 11,18-diHEPE, 12,18-diHEPE, and 17,18-diHEPE, respectively, from the MRM channel, and from that they were 18-HEPE-dependently recognized.
- a plurality of peaks are recognized regarding some channels, and it is thought to be due to difference in coordination of a double bond (cis, trans), and difference in steric configuration of a hydroxyl group (S body, R body).
- Zymosan A (Wako Pure Chemical Industries, Ltd.) was suspended in a physiological saline at a concentration of 1 mg/mL, and the suspension was warmed at 37° C. for 30 minutes.
- This zymosan A suspension (1 mL) was intraperitoneally administered to a C57BL/6J mouse (wild-type; 8 to 10 weeks old, female; Japan SLC, Inc.). After 48 hours, cells which had exuded into an abdominal cavity were recovered, and the cell number was counted. Centrifugation was performed at 1200 rpm and 4° C. for 5 minutes and the supernatant (exudate) was stored at ⁇ 20° C.
- a precipitate (cells) was suspended in PBS, the suspension was passed through a 70 ⁇ m and 38 ⁇ m mesh, and an eosinophil population was selected by FACS Aria (BD Biosciences).
- MRM is a measuring procedure of detecting specifically a compound from a combination of a MS value of a compound (Q1) and a MS/MS value characteristic in a structure (Q3).
- Metabolites derived from 18-HEPE identified in the present specification are such that MS values upon measurement in a negative ion mode are all equal, being 333 in which one oxygen is added to 18-HEPE, but structure-specific MS/MS values are different depending on a position at which oxygen is added.
- LC condition was as follows:
- RvE1, RvE2 and 10,20-diHDoHE are produced by 5-LOX which is mainly highly expressed in eosinophil, while it was made clear that all of four 18-HEPE-derived novel metabolites (8,18-diHEPE, 11,18-diHEPE, 12,18-diHEPE and 17,18-diHEPE) identified in the present specification, as well as 13,20-diHDoHE, 14,20-diHDoHE and 19,20-diHDoHE are produced by enzymes other than 5-LOX ( FIGS. 2F and 2G ).
- novel compounds corresponding to novel metabolites derived from 18-HEPE and 20-HDoPE can be synthesized. It was found out that these are produced by 12/15-LOX or soybean LOX (sLOX), as a result of intensive study. Then, in order to assess activity of these metabolites, those metabolites were tried to synthesize using an enzymatic reaction therefor. In the present Example, an enzymatic reaction was performed using sLOX for the purpose of subjecting to general use, in place of mouse 12/15-LOX. In addition, whether produced metabolites were constituent with those produced by a living body was examined by a spike experiment.
- DHA SIGMA: Stored at ⁇ 20° C. as 100 mg/mL methanol (Wako Pure Chemical Industries, Ltd.) solution.
- Methyl formate Wako Pure Chemical Industries, Ltd.
- Hydrochloric acid Wako Pure Chemical Industries, Ltd.: Diluted with milliQ to 1N, and stored at room temperature.
- Acetic acid (Wako Pure Chemical Industries, Ltd.) was added to 0.01% v/v acetic acid: milliQ (pure water) to 0.01% v/v.
- 18-HEPE (Cayman) (300 ⁇ g) was taken into an eggplant flask, a solvent was vaporized with nitrogen, and 9 mL of a borate buffer (50 mM of each of boric acid and potassium chloride, pH 9.0) was added thereto to dissolve it.
- SIGMA Soybean lipoxygenase
- the condition of reverse phase HPLC was as follows:
- peaks 5 and 6 which are 17,18-diHEPE
- a spike experiment with a biological sample sample from incubation of PEC after 48 h from peritonitis inducement with 18-HEPE
- these peaks were consistent with two major peaks of a channel for specifically detecting 17,18-diHEPE ( FIG. 3D ). It is thought that two isoforms of 17,18-diHEPE obtained by the enzymatic reaction are the same as those produced by a living body. It is expected that 11,18-diHEPE is similarly synthesized.
- PBS Phosphate buffered physiological saline
- FITC anti-mouse F4/80 (0.5 mg/mL): eBiosciences
- the antibodies are diluted in 50 ⁇ L/sample PBS. Preparation at use.
- zymosan peritonitis elicited by intraperitoneally administering zymosan being a cell wall component of yeast was used. Since an exudate in an abdominal cavity can be recovered, the present model is a model suitable for analyzing cytokines and eicosanoids.
- Zymosan A (Wako Pure Chemical Industries, Ltd.) was suspended in a physiological saline to 1 mg/mL, and the suspension was warmed at 37° C. for 30 minutes. Thereafter, this zymosan A solution was vortexed, and returned to room temperature.
- 17,18-diHEPE was taken into a 1.5 mL tube, and a solvent was vaporized with nitrogen to complete dryness and, thereafter, a physiological saline was added to dissolve it. Then, 100 ⁇ L of this compound solution was injected (1 ng or 10 ng/mouse) through a tail vein of C57BL/6J mouse (7 weeks old, mail: CLEA Japan, Inc.).
- a group in which only a physiological saline was injected, and a group in which dexamethasone (10 ⁇ g/mouse) being an anti-inflammatory steroid was injected were used. After about 2 minutes, 1 mL of a zymosan A solution was intraperitoneally administered. After 2 hours, cells exuded into an abdominal cavity were recovered into a tube with a PBS, and the cell number was counted. Thereafter, this tube was centrifuged at 1200 rpm and 4° C. for 5 minutes to remove the supernatant, a precipitate (pellet) was suspended in PBS, and a population was analyzed by three-color staining of FACS.
- Abdominal cavity cells were adjusted to 2.5 ⁇ 10 6 cells/mL, and 200 ⁇ L was placed into a 5 mL round-bottom tube (BDFalcon) (5 ⁇ 10 5 cells/tube). To this tube was added an anti-mouse CD16/CD32 antibody (0.5 mg/mL; BDBiosciences) at 1 ⁇ L per tube, and this was incubated at room temperature for 10 minutes.
- BDFalcon round-bottom tube
- a staining antibody mix prepared by diluting 1.0 ⁇ L of FITC bound anti-mouse F4/80 antibody (0.5 mg/mL; eBiosciences), 0.5 ⁇ L of PE bound anti-mouse Ly-6G & Ly-6C antibody (0.2 mg/mL; eBiosciences) and 0.5 ⁇ L of PerCP-Cy5.5 bound anti-mouse CD11b antibody (0.2 mg/mL; eBiosciences) in 50 ⁇ L of PBS, per sample) at 50 ⁇ L/tube, and this was incubated at room temperature for 15 minutes under light shielding. Measurement was performed by FACS Calibur (BDBiosciences).
- Results are shown in FIG. 4B .
- IC 40 This is expressed as IC 40 as in FIG. 4F .
- IC 40 was calculated to be approximately 8 ng. Since in the conventional compound, at highest around 100 ng was strongest, this results in that the compound of the present invention exhibits neutrophil suppressing activity which is one order or more stronger than the conventional activity.
- the compound of the present invention is produced using a recombinant enzyme expressing mouse 12/15-LOX or platelet-type 12-LOX in Escherichia coli in place of sLOX in Example 3.
- a recombinant enzyme can be produced using the technique well-known in the art (e.g., Sambrook J. et al. which is incorporated into the present specification etc.) for recombinant technique etc., with reference to information regarding enzymes in Yoshimoto T. et al. Prostaglandins and Other Lipid Mediators Vol. 68-69, 245-262 (2002) for platelet type 12-LOX, and Kuhn H. et al. Prostaglandins and Other Lipid Mediators Vol. 68-69, 263-290 (2002) for lymphocyte-type 12/15-LOX.
- the compound of the present invention can be synthesized.
- HDoPA is used as a raw material, it is expected that 13,20-diHDoPE, 14,20-diHDoPE, and 19,20-diHDoPE are produced.
- Example 5 Activity of substances produced in Example 5 is measured based on the protocol described in Example 4.
- neutrophil suppressing activities of 8,18-diHEPE, 12,18-diHEPE, 17,18-diHEPE, 13,20-diHDoPE, 14,20-diHDoPE, and 19,20-diHDoPE can be measured.
- Escherichia coli with a gene introduced therein was cultured on a LB medium, IPTG was added to 1 mM, and a protein was induced at 15° C.
- Escherichia coli after inducement was ground, and the centrifuged supernatant was subjected to a nickel column to purify an objective protein.
- Acetic acid (Wako Pure Chemical Industries, Ltd.) was added to 0.01% v/v acetic acid: milliQ (pure water) to 0.01% v/v.
- 18-HEPE or 20-HDoHE was taken into a reactor, a solvent was vaporized with nitrogen, and PBS was added thereto so that a concentration of 18-HEPE or 20-HDoHE was 30 ⁇ g/mL, to dissolve the material.
- 8-LOX was added thereto to 0.1 mg/mL to progress an enzymatic reaction and, thereafter, a reducing reaction was performed using NaBH 4 . Thereafter, a fraction of a fatty acid metabolite was prepared by solid phase extraction.
- HPLC Align Technologies
- peaks were fractionated into glass small test tubes.
- a solvent was evaporated with nitrogen to dryness, and the fractions were finally stored as an ethanol solution at ⁇ 20° C.
- the condition of reverse phase HPLC was as follows:
- the compound of the present invention is produced using, as a substrate, 12-HpEPE and 14-HpDoHE in place of 18-HEPE and 20-HDoHE.
- Acetic acid (Wako Pure Chemical Industries, Ltd.) was added to 0.01% v/v acetic acid: milliQ (pure water) to 0.01% v/v.
- 12-HpEPE or 14-HpDoHE was taken into a reactor, a solvent was vaporized with nitrogen, and a borate buffer was added thereto so that a concentration of 12-HpEPE or 14-HpDoHE was 30 ⁇ g/mL, to dissolve it. Then, sLOX was added thereto to 0.1 mg/mL to progress an enzymatic reaction and, thereafter, a reducing reaction was performed using NaBH 4 . Thereafter, a fraction of a fatty acid metabolite was prepared by solid phase extraction.
- HPLC Align Technologies
- peaks were fractionated into glass small test tubes.
- a solvent was vaporized with nitrogen to dryness, and the product was finally stored as an ethanol solution at ⁇ 20° C.
- the condition of reverse phase HPLC was as follows:
- PBS Phosphate buffered physiological saline
- Resolvin E2 (RvE2): This was prepared according to Ogawa S. et al., Org. Lett. 11, 3602-3605 (2009).
- zymosan peritonitis elicited by intraperitoneally administering zymosan being a cell wall component of yeast was used. Since the present model can recover an exudate in an abdominal cavity, it is a model suitable for analyzing cytokines and eicosanoids.
- Zymosan A (Wako Pure Chemical Industries, Ltd.) was suspended in a physiological saline to 1 mg/mL, and the suspension was warmed at 37° C. for 30 minutes. Thereafter, this zymosan A solution was vortexed, and returned to room temperature. Various compounds were taken into a 1.5 mL tube, a solvent was vaporized with nitrogen to complete dryness, and a physiological saline was added to dissolve the compound.
- Eosinophil was purified from human peripheral blood using the known technique. Specifically, neutrophil was removed and separated from a granulocyte fraction obtained from peripheral blood using CD16 Microbeads (Miltenyl Biotec) (Hansel et al. (1991) J. Immunol. Methods 145, 105-110). This human eosinophil was stimulated by adding 10 ⁇ M of 18-HEPE or 20-HDoHE to 1.0 ⁇ 10 6 cells/ml in HESS, and adding 10 ⁇ M of calcium ionophore A23187 (SIGMA), ice-cooled methanol was added after 30 minutes to stop the reaction, and solid phase extraction was performed. Solid phase extraction was performed as described in Examples etc.
- the compound of the present invention is present in a living body also in human.
- the compound of the present invention can be produced not only by mouse eosinophil, but also by human eosinophil.
- Neutrophil is isolated from human peripheral blood (see Serhan C. N. et al. Biochemistry. 34, 14609-14615 (1995)), mixed into a culturing solution (RPMI-0.1% BSA) to which a target compound has been added, to 3 ⁇ 10 5 cells/200 ⁇ l, and this is incubated at 37° C. for 15 minutes. Thereafter, this is transferred to a cell culture insert (24 well, 3 ⁇ m pore; manufactured by Falcon), LTB4 (5 nM) as a chemotactic factor is added to a lower layer, and the number of neutrophil transferred to a lower layer after 2 hours is measured.
- RPMI-0.1% BSA a culturing solution
- the compound of the present invention can be discussed as follows.
- the compound of the present invention exhibits neutrophil suppression in vitro and in vivo. Therefore, the pharmaceutical composition of the present invention can be used as an agent for preventing and/or treating diseases such as encephalitis, myelitis and encephalomyelitis, meningitis, inflammatory multiple neuropathy, neuritis, dacryoadenitis, orbital inflammation, conjunctivitis (allergic conjunctivitis, spring keratoconjuctivitis etc.), keratitis, chorioretinal scar, endophthalmitis, retrobulbar neuritis, retinopathy, glaucoma, cellulitis, external otitis, perichondritis, tympanitis, salpingitis, mastoiditis, myringitis, labyrinthitis, pulpitis, periodontitis, sialitis, stomatitis, glossitis
- diseases such as encepha
- the solubility of a compound can be determined under the condition of addition of 1% DMSO.
- a 10 mmol/L compound solution is prepared with DMSO, and 6 ⁇ L of the compound solution can be added to 594 ⁇ L of an artificial intestine fluid having a pH of 6.8 (118 mL of a 0.2 mol/L sodium hydroxide (NaOH) test solution, and water was added to 250 mL of a 0.2 mol/L dihydrogen potassium phosphate test solution to 1000 mL).
- a mixed solution can be suction-filtered.
- a subject compound is reacted for a certain time, a remaining rate is calculated by comparison between the reacted sample and unreacted sample, and a degree metabolized in liver can be assessed.
- a reaction can be performed at 37° C. for 0 minutes or 30 minutes in the presence of 1 mmol/L NADPH, in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing human hepatic microsome 0.5 mg protein/mL (oxidative reaction).
- a test compound in the centrifugation supernatant can be quantitated by LC/MS/MS, and a remaining rate of the test compound after the reaction for 30 minutes can be calculated by assuming that a compound amount at 0 minutes reaction time is 100%.
- a degree of inhibition of each metabolite production amount by a test compound can be assessed using, as an index, O-deethylation of 7-ethoxyresoruf in (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenyloin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), hydroxylation of terfenadine (CYP3A4) as a typical substrate metabolism reaction of human main CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4).
- the reaction condition is as follows: substrate, 0.5 ⁇ mol/L ethoxyresoruf in (CYP1A2), 100 ⁇ mol/L tolbutamide (CYP2C9), 50 ⁇ mol/L S-mephenyloin (CYP2C19), 5 ⁇ mol/L dextromethorphan (CYP2D6), 1 ⁇ mol/L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; test drug concentration, 1, 5, 10, 20 ⁇ mol/L (4 points).
- resorufin CYP1A2 metabolite
- CYP1A2 metabolite resorufin in the centrifugation supernatant
- a fluorescent multilabel counter a fluorescent multilabel counter
- tolbutamide hydroxide body CYP2C9 metabolite
- mephenyloin 4′-hydroxide body CYP2C19 metabolite
- dextromethorphan CYP2D6 metabolite
- terfenadine alcohol body CYP3A4 metabolite
- a sample in which only DMSO being a solvent for dissolving a drug can be added to a reaction system is defined as a control (100%), remaining activity (%) at each concentration at which a test drug solution is added, is calculated, and IC 50 can be calculated by reverse presumption with a logistic model using a concentration and a suppression rate.
- a CYP3A4 fluorescent MBI test is a test which examines potentiation of CYP3A4 inhibition of a compound by a metabolism reaction, Escherichia coli -expressing CYP3A4 is used as an enzyme, 7-benzyloxytrifluoromethylcoumarine (7-BFC) is debenzylated with the CYP3A4 enzyme, and the test is performed using, as an index, a reaction which generates a metabolite which emits fluorescence, 7-hydroxytrifluoromethylcoumarine (HFC).
- the reaction condition is as follows: substrate, 5.6 ⁇ mol/L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature 25° C. (room temperature); CYP3A4 content ( Escherichia coli -expressing enzyme), 62.5 pmol/mL at pre-reaction, 6.25 pmol/mL at reaction (at 10-fold dilution); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol/L (6 points).
- a K-Pi buffer pH 7.4
- NADPH is also added to a remaining pre-reaction solution to initiate a pre-reaction (presence of pre-reaction) and, after a pre-reaction for a predetermined time, a part thereof is transferred to another plate so that it is 1/10 diluted with a substrate and a K-Pi buffer, thereby, a reaction as an index can be initiated.
- a sample in which only DMSO being a solvent with a drug dissolved therein is added to a reaction system is defined as a control (100%), and remaining activity (%) at each concentration at which a test drug solution is added is calculated, and IC 50 can be calculated by reverse presumption with a logistic model using a concentration and a suppression rate.
- a difference in an IC 50 value is 5 ⁇ mol/L or more can be (+), and the case where the difference is 3 ⁇ mol/L or less can be ( ⁇ ).
- a bacterium cell solution is centrifuged (2000 ⁇ g, 10 minutes) to remove a culturing solution, and a bacterium is suspended in 9 mL of a Micro F buffer (hydrogen dipotassium phosphate (K 2 NPO 4 ): 3.5 g/L, dihydrogen potassium phosphate (KH 2 PO 4 ): 1 g/L, ammonium sulfate ((NH 4 ) 2 SO 4 ): 1 g/L, trisodium citrate dihydrate: 0.25 g/L, magnesium sulfate heptahydrate (MgSO 4 .7H 2 O): 0.1 g/L), and this is added to 110 mL of an Exposure medium (Micro F buffer containing biotin: 8 ⁇ g/mL, histidine: 0.2 ⁇ g/mL, and glucose: 8 mg/mL) and, for the TA100 strain, 3.16 mL of a Micro F buffer (hydrogen dipotassium
- a bacterium cell solution in which a test substance can be exposed is admixed with 2300 ⁇ L of an Indicator medium (Micro F buffer containing biotin: 8 ⁇ g/mL, histidine: 0.2 ⁇ g/mL, glucose: 8 mg/mL, bromocresol purple: 37.5 ⁇ g/mL), each 50 ⁇ L is dispensed in microplate 48 wells/dose, and this is subjected to static culturing at 37° C. for 3 days.
- an Indicator medium Micro F buffer containing biotin: 8 ⁇ g/mL, histidine: 0.2 ⁇ g/mL, glucose: 8 mg/mL, bromocresol purple: 37.5 ⁇ g/mL
- a well containing a bacterium which has acquired the proliferation ability by mutation of an amino acid (histidine) synthesizing enzyme gene turns from purple to yellow by pH change
- a bacterium proliferating well which can turn to yellow in 48 wells per dose is counted and can be assessed by comparing with a negative control group. Assessment can be performed by indicating negative mutagenicity as ( ⁇ ), and positive mutagenicity as (+).
- a cell is retained at a membrane potential of ⁇ 80 mV by a whole cell patch clamp method and, thereafter, I Kr which induced when depolarization stimulation at +50 mV is given for 2 seconds and, further, repolarization stimulation at ⁇ 50 mV is given for 2 seconds is recorded.
- an absolute value of a maximum tail current can be measured using a current value at a retained membrane potential as a standard, and employing an analysis software (DataXpress ver. 1, Molecular Devices Corporation). Further, an inhibition rate relative to a maximum tail current before application of a test substance is calculated, this is compared with a medium application group (0.1% dimethyl sulfoxide solution), and influence of the test substance on I Kr can be assessed. The result can indicate an inhibition rate at a compound concentration of 1 ⁇ mol/L.
- Oral absorbability can be performed using the following BA test.
- Animal to be used A rat or a mouse was used.
- a predetermined dose was administered orally or intravenously.
- a group was set as follows (a dose varied for every compound).
- Administration method For oral administration, the administration solution was forcibly administered to stomach by oral sonde. For intravenous administration, the administration solution was administered with a syringe equipped with an injection needle through a tail vein. (6) Assessment item: Blood was collected with time, and a plasma drug concentration was measured using LC/MS/MS. (7) Statistical analysis: Regarding plasma concentration transition, an area under a plasma concentration-time curve (AUC was calculated using a non-linear minimum square method program WinNonlin (registered trademark), and bioavailability (BA) was calculated from AUC of an oral-administered group and an intervenous-administered group.
- AUC area under a plasma concentration-time curve
- BA bioavailability
- the results can be indicated, for example, as a BA value at oral administration 1 mg/kg in a rat.
- tablets consisting of the following composition are produced by the ordinary method.
- powders consisting of the following composition are produced by the ordinary method.
- syrups consisting of the following composition are produced by the ordinary method.
- the present invention provides a medicament for treating a disease or a disorder associated with neutrophil suppression, a compound used therefor, a pharmaceutically acceptable salt thereof, or a prodrug such as a hydrate thereof.
- the compound of the present invention exhibits excellent neutrophil suppression activity as described in the present specification. Therefore, the present invention is useful in the pharmaceutical industry.
Abstract
Description
- Non-Patent Document 1: Singh G. Am. J. Med. 105, 31S-38S (1998)
- Non-Patent Document 2: Funk C. D. and FitzGerald G. A. J. Cardiovasc Pharmacol 50, 470-479 (2007)
- Non-Patent Document 3: Serhan C. N. et al. Prostaglandins and other Lipid Mediators 73, 155-172 (2004)
- Non-Patent Document 4: E. Tjonahen et al., Chemistry & Biology 13, 1193-1202, November 2006
(3) A neutrophil suppressing agent comprising the compound or pharmaceutically acceptable salt or solvate according to
(4) A pharmaceutical comprising the compound or pharmaceutically acceptable salt or solvate according to
(5) The pharmaceutical according to
(6) A method of producing the compound or pharmaceutically acceptable salt or solvate according to
-
- 30 to 33 minutes→80 μL/minute.
- 33 to 45 minutes→100 μL/minute.
(Production of Calibration Curve Using Standard Compounds)
Sodium tetrahydroborate (NaBH4): Wako Pure Chemical Industries, Ltd.
18-HEPE and 20-HDoHE: Cayman
(2. Purification of Compound Using Reverse Phase HPLC)
Soybean lipoxygenase (sLOX): SIGMA
Sodium tetrahydroborate (NaBH4): Wako Pure Chemical Industries, Ltd.
12-HpEPE and 14-HpDoHE: EPA and DHA were reacted with mouse 12-LOX (prepared as mouse 8-LOX of Example 7), respectively, and the products were extracted, and prepared.
(2. Purification of Compound Using Reverse Phase HPLC)
(6) Assessment item: Blood was collected with time, and a plasma drug concentration was measured using LC/MS/MS.
(7) Statistical analysis: Regarding plasma concentration transition, an area under a plasma concentration-time curve (AUC was calculated using a non-linear minimum square method program WinNonlin (registered trademark), and bioavailability (BA) was calculated from AUC of an oral-administered group and an intervenous-administered group.
Compound of the |
100 | | ||
Lactose | ||||
60 | | |||
Potato starch | ||||
30 | | |||
Polyvinyl alcohol | ||||
2 | | |||
Magnesium stearate | ||||
1 | mg |
Tar dye | Minor amount | ||
Compound of the |
150 | mg | ||
Lactose | 280 | mg | ||
Compound of the |
100 | mg | ||
Purified white sugar | 40 | g | ||
Ethyl p- |
40 | mg | ||
Propyl p- |
10 | mg | ||
Chocolate flavor | 0.1 | cc | ||
Claims (14)
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JP5523439B2 (en) | 2014-06-18 |
EP2415748A4 (en) | 2013-08-07 |
TW201039829A (en) | 2010-11-16 |
JPWO2010095706A1 (en) | 2012-08-30 |
WO2010095706A1 (en) | 2010-08-26 |
US20120059061A1 (en) | 2012-03-08 |
EP2415748A1 (en) | 2012-02-08 |
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